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\begin{document}

\title{Is Autism a PIN1 Deficiency Syndrome? A Proposed Etiological
Role for Glyphosate}



\author[1]{Stephanie Seneff}%
\author[1]{Anthony M Kyriakopoulos}%
\author[1]{Greg Nigh}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 17, 2024}


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Stephanie Seneff \textsuperscript{1*}, Anthony M
Kyriakopoulos\textsuperscript{2}, Greg Nigh\textsuperscript{3}

\begin{enumerate}
\tightlist
\item
  Senior Research Scientist, Computer Science and Artificial
  Intelligence Laboratory, Massachusetts Institute of Technology,
  Cambridge MA USA; seneff@csail.mit.edu.
\item
  Director and Head of Research and Development, Nasco AD Biotechnology
  Laboratory, Department of Re-search and Development, Sachtouri 11,
  18536, Piraeus, Greece; Antkyriak@gmail.com.
\item
  Naturopathic Oncologist, Immersion Health, Portland, OR 97214, USA;
  drnigh@immersionhealthpdx.com.
\end{enumerate}

* Corresponding author: Stephanie Seneff. Email: seneff@csail.mit.edu.

\textbf{Abstract}

Autism is a neurodevelopmental disorder whose prevalence has increased
dramatically in the United States over the past two decades. It is
characterized by stereotyped behaviors and impairments in social
interaction and communication. In this paper, we present evidence that
autism can be viewed as a PIN1 deficiency syndrome. PIN1 (Peptidylprolyl
Cis/Trans Isomerase, NIMA-Interacting 1) is a peptidylprolyl cis/trans
isomerase, and it has widespread influences in biological organisms.
Broadly speaking, PIN1 deficiency is linked to many neurodegenerative
diseases, whereas PIN1 overexpression is linked to cancer. Death
associated protein kinase 1 (DAPK1) strongly inhibits PIN1, and the
hormone melatonin inhibits DAPK1. Melatonin deficiency is strongly
linked to autism. It has recently been shown that glyphosate exposure to
rats inhibits melatonin synthesis due to increased glutamate release
from glial cells and increased expression of metabotropic glutamate
receptors. Glyphosate's inhibition of melatonin leads to a reduction in
PIN1 availability in neurons. In this paper, we show that PIN1
deficiency can explain many of the unique morphological features of
autism, including increased dendritic spine density, missing or thin
corpus callosum and reduced bone density. We show how PIN1 deficiency
disrupts the functioning of powerful high level signaling molecules,
such as nuclear factor erythroid 2-related factor 2 (NRF2) and p53.
Dysregulation of both of these proteins has been linked to autism.
Severe depletion of glutathione in the brain resulting from chronic
exposure to oxidative stressors and extracellular glutamate leads to
oxidation of the cysteine residue in PIN1, inactivating the protein and
further contributing to PIN1 deficiency. Impaired autophagy leads to
increased sensitivity of neurons to ferroptosis. Finally, we consider
evidence of the potential toxic effects of the mRNA SARS-CoV-2 vaccines
in the light of metabolic defects in autism, and we propose that
children with autism would be especially sensitive to damage from the
vaccines.

\textbf{Keywords}

Autism, PIN1, glyphosate, apoptosis, mRNA vaccines, DAPK1, melatonin,
glutathione, NRF2, p53.

\textbf{Introduction}

Autism is a neurodevelopmental disorder characterized mainly by impaired
social interactions, repetitive behaviors, and limited verbal
communications {[}1{]}. It is also associated with an increased risk to
a host of emotional and psychological conditions, including depression,
anxiety, gender dysphoria, schizophrenia, catatonia, and psychosis
{[}2{]}. While genetics plays a role in autism risk, environmental
exposures are likely driving the epidemic. Environmental toxicants
induce inflammation, oxidative stress, and mitochondrial dysfunction in
the brain, leading to neuropathology {[}3{]}. Environmental risk factors
include air pollution, nutritional deficiencies, pesticides, toxic metal
exposures, infection, and brain trauma {[}3-8{]}.

Early diagnosis of autism has presented a significant challenge to
clinicians for decades {[}9{]}. It is generally recognized that autism
diagnoses can be divided into two categories: children diagnosed before
age two (early-onset autism) and those diagnosed after age two
(regressive autism). There is some evidence that children with
regressive autism exhibit behaviors prior to regression that are
predictive of it {[}10,11{]}. That said, another study showed that
nearly half of the cases of regressive autism have no such discernible
behaviors -- the child regresses after a previously normal developmental
phase {[}12{]}.

Through the main body of this paper, we will describe in detail the
mechanistic links we believe exist between glyphosate exposure and the
myriad pathological changes found in the brain and other systems of
children with autism. We will forego a discussion of the early vs
regressive autism until near the end, where we will show how our
exposure model of autism etiology can shed light on the mystery around
autism's variable childhood age of onset.

The prevalence of autism has increased dramatically over the past two
decades in the United States, strongly correlated with the dramatic rise
in the use of glyphosate, the active ingredient in the herbicide
Roundup, on core crops {[}13{]}. While correlation does not prove
causation, there is now significant evidence that glyphosate causes
neurodevelopmental problems, lending strength to the temporal
correlations. In an epidemiological study, children who were born within
2000m of an agricultural source of glyphosate had a significantly
increased risk to developing autism {[}14{]} While many other factors,
both genetic and environmental, contribute to autism, we will show that
glyphosate may be the most significant cause of the epidemic {[}13{]}.

One of the known causes of autism is maternal immune activation (MIA)
due to infection during pregnancy. Studies have shown that behavioral
abnormalities in the offspring of rodents following MIA are
characteristic of schizophrenia and autism {[}15{]}. Perturbations of
the mother's gut microbiota during pregnancy can induce autism-like
behaviors in mice {[}16{]}. Maternal glyphosate exposure at low doses
has been shown to cause MIA in pregnant mice, associated with
autism-like behaviors in the offspring, through increased expression of
soluble epoxide hydrolase (sEH) {[}17{]}. Inflammation in the brain
upregulates the expression of sEH, an enzyme that oxidizes
polyunsaturated fatty acids (PUFAs) {[}15{]}. It has been proposed that
prophylactic treatment to suppress the expression of sEH could be a
beneficial treatment option for autism {[}17{]}.

The human brain accounts for only 2\% of the body mass but consumes 20\%
of the oxygen. It also has high amounts of PUFAs that are susceptible to
oxidative damage through lipid peroxidation, leading to mitochondrial
dysfunction {[}18{]}. Children naturally have low levels of glutathione,
and glutathione deficiency is a common feature associated with autism,
along with increased oxidative stress in the brain {[}19{]}. Several
oxidative stress markers, such as lipid peroxides, malondialdehyde
(MDA), protein carbonyls and 3-nitrotyrosine, are elevated in
association with autism, and correlated with autism severity {[}20{]}.

A study comparing children with autism against normal controls found a
significant block in cystathionine formation associated with an
accumulation of homocysteine and low levels of the essential
antioxidant, glutathione. A low level of urinary methionine and
S-adenosyl methionine (SAMe) indicates deficiencies in methylation
pathways. A significant number of the children who were studied showed
deficiencies in three B vitamins: B6 (pyridoxine), B9 (folate), and B12
(cobalamin) {[}21{]}. The conversion of homocysteine to cysteine in the
transsulfuration pathway depends on pyridoxine as a cofactor {[}22{]}.
The synthesis of methionine from cysteine depends on both folate and
methylcobalamin {[}23{]}. Cultured neurons are protected from
glutamate-induced neurotoxicity by administration of methylcobalamin,
likely through membrane alteration by SAMe {[}24{]}.

An impaired sulfation pathway was first recognized as a risk factor in
autism in a paper published by Waring and Klovrza al. in 2000 {[}25{]}.
Cystathionine \selectlanguage{greek}β-\selectlanguage{english}synthase converts homocysteine to cystathionine, and
this is the rate-limiting step of the transsulfuration pathway,
ultimately producing sulfate and phosphoadenosine phosphosulfate (PAPS),
the universal sulfate donor. Both ascorbate (vitamin C) and retinoic
acid (vitamin A) are cofactors in this pathway, as shown in detail by
McCully in 2011 {[}26{]}. Both ascorbate and retinoic acid have been
shown to have therapeutic value in treating autism. In a study published
in 2018, vitamin A deficiency was found in 78\% of autistic children,
and vitamin A supplementation improved autistic symptoms {[}27{]}. In a
genetic mouse model of autism, retinoic acid treatment rescued social
deficits {[}28{]}. In a valproate-induced mouse model of autism,
prenatal exposure to ascorbate attenuated the effects of valproate on
the autistic behaviors of the pups {[}29{]}. A paper published by
Alvarez-Moya et al. in 2022 showed conclusively that glyphosate is
genotoxic to erythrocytes of salamanders and tilapia, as well as human
lymphocytes. They also showed that supplementation with ascorbate and
resveratrol (an antioxidant) reduced glyphosate's genotoxic effects
{[}30{]}.

Children with autism commonly have sleep disorders and dysregulated
circadian rhythms, suggesting disturbances in melatonin metabolism
{[}31{]}. Melatonin is enzymatically degraded in the liver to
6-hydroxymelatonin and excreted in the urine as 6-sulfatoxymelatonin
{[}32{]}. Several studies have shown that nocturnal levels of
6-sulfatoxymelatonin are significantly reduced in association with
autism {[}33,34{]}, likely due to impaired melatonin synthesis in the
pineal gland. Melatonin is synthesized in the pineal gland from
serotonin, through the addition of both an acetyl group and a methyl
group. Serotonin is derived from the amino acid tryptophan, a product of
the shikimate pathway in plants and microbes. Glyphosate's primary
mechanism of toxicity in plants is believed to be its suppression of the
shikimate pathway {[}35,36{]}. Therefore, glyphosate likely interferes
with tryptophan synthesis by the gut microbes. Mice with a null mutation
in the enzyme tryptophan hydroxylase (and therefore severely deficient
in brain serotonin) displayed multiple characteristic features of autism
{[}37{]}. S-adenosyl methionine is the source of the methyl group, so
its deficiency would likely also lead to a deficiency in melatonin
{[}38{]}. Importantly, glyphosate exposure to rats prenatally and
perinatally caused a 43\% reduction in serum melatonin levels measured
after the rat pups had matured, likely through epigenetic effects
{[}39{]}.

A remarkable postmortem study showed disturbingly low levels of various
cobalamin conjugates in autistic brains {[}40{]}. The authors measured
levels of five different cobalamin species: hydroxycobalamin,
methylcobalamin, adenosylcobalamin, cyanocobalamin, and
glutathionylcobalamin. All of the conjugated cobalamins were
significantly reduced in association with autism, particularly
glutathionylcobalamin, which could be due in part to a deficiency in
glutathione. Glutathionylcobalamin is an intermediate in the formation
of methylcobalamin {[}41{]}. Methylcobalamin injections increase
production of melatonin by the rat pineal gland, indicating a dependency
on methylcobalamin to catalyze melatonin synthesis {[}42{]}.

Proline is one of the 20 coding amino acids, and it has unique
properties that play a powerful role in biology. Proline is the only
coding amino acid that exists in two different isomers (cis- and
trans-), which contain the exact same molecular formula but with
different arrangements in space. Interestingly, proline can
spontaneously switch back and forth between cis- and trans- isomers when
it is embedded in a peptide sequence, although this happens
infrequently. There is a class of enzymes called peptidylprolyl
isomerases (PPIases) that catalyze the switch, and, when active, they
can increase the rate of flipping from a cis- to a trans- isoform of
proline by a factor of 1,000 {[}43{]}.

PPIase NIMA-Interacting 1 (PIN1) is a member of the class of PPIases,
and it has diverse roles in human development and the response to
cellular stressors. It acts as a molecular switch by inducing
conformational changes in the affected protein by isomerizing prolines
{[}44{]}. Prolyl isomerization is involved in many cellular processes,
including apoptosis, mitosis, cell signaling, ion channel gating,
amyloidogenesis and neurodegeneration {[}45{]}. PIN1 regulates the
function of several powerful signaling proteins, including catalytic
activity, phosphorylation status, protein interactions, subcellular
location and protein stability {[}46,47{]}. It plays a central role in
phosphorylation pathways, which regulate many aspects of cellular
activities in response to stressors, including the DNA damage response,
antioxidant defenses, and programmed death. It is also involved in the
balance between excitatory and inhibitory neurotransmitter responses,
and in the maturation of neurons during early life {[}48{]}. PIN1 is
overexpressed in association with many cancers {[}49{]}. By contrast, it
is under-expressed in association with many neurogenerative diseases
{[}48{]}.

PIN1 has a very specific function, which is to switch a proline residue
preceded by serine or threonine from the cis- to the trans- isomer. It
is only active when the preceding serine or threonine is phosphorylated.
Furthermore, enzymes that dephosphorylate the preceding residue,
particularly protein phosphatase 2A (PP2A), are only active when the
proline is in the trans- state {[}50{]}. Thus, removal of the phosphate
anion depends upon PIN1's activity in maintaining the proline residue in
the trans- configuration. This remarkably complex epigenetic effect has
powerful influences on both the activity of the altered protein and its
localization within the cell (e.g., nucleus or mitochondria). Protein
phosphorylation is probably the most common post-translational
modification in proteins, and 96\% of the phosphorylations are applied
to the (Ser/Thr)-Pro motif {[}51{]}.

In this paper, we will develop the argument that autism can be
characterized as a PIN1 deficiency syndrome. We will show that many of
the neurodevelopmental defects and morphological features of autism are
linked to PIN1 deficiency. We also argue that the disruptions in
synaptic signaling linked to autism can be explained by PIN1 deficiency.
Many of the genetic links to autism involve proteins that are regulated
by PIN1. We provide substantial evidence from the research literature
that glyphosate's mechanisms of toxicity can be expected to suppress
PIN1 activity, either directly through cysteine oxidation by reactive
oxygen species induced by glyphosate, or via suppression of melatonin
synthesis, resulting in DAPK1 overexpression. This effect can explain
its link to the autism epidemic. Finally, we hypothesize that autistic
children are likely to be highly sensitive to the mRNA vaccines, as many
of the toxic effects of the vaccine induce metabolic disruptions that
are already ongoing in the autistic brain.

\textbf{Glyphosate and Autism}

Gut dysbiosis plays a role in many neurological diseases, including
depression, Alzheimer's disease, Parkinson's disease, and autism
{[}52{]}. There has been growing awareness recently regarding the
complex interactions between the gut microbiome and the brain via the
highly interconnected gut-brain axis, a bidirectional communication
network {[}53{]}. Exposure to glyphosate reduces the abundance of a
number of different acid-loving species that produce short chain fatty
acids (SCFAs) from dietary fiber {[}54{]}. The SCFA butyrate delivered
to the liver via the hepatic portal vein is detected by sensors in the
liver, and a signal is conveyed to nerve centers in the brain via the
vagus nerve which enhances sleep quality {[}55{]}. Sleep disorder is a
prominent feature of autism {[}56{]}. As we mentioned earlier, melatonin
deficiency caused by glyphosate likely also plays a role {[}39{]}.

Butyrate induces the differentiation of immune cells into T-regulatory
cells (Tregs), which control inflammation {[}51{]}. The prevalence of
inflammatory bowel disease (IBD) has increased over time closely in step
with the rise in glyphosate usage on core crops {[}57{]}. Glyphosate was
one of the toxic chemicals identified as a contributor to IBD in a
recent publication by Chen et al. {[}58{]}. Children with autism are at
a significant increased risk to IBD, with an odds ratio (OR) of 1.66 (p
\textless{} 0.001) {[}59{]}.

Glyphosate exposure to rats for 35 days led to multiple disruptions in
the gut. Glyphosate resulted in a decrease in the ratio of villus height
to crypt depth in the duodenum and jejunum, a feature associated with
celiac disease {[}60{]}. In this experiment, glyphosate also caused a
decrease in glutathione levels and the activity of antioxidant enzymes,
including glutathione peroxidase (Gpx). MDA content was also elevated,
indicating PUFA peroxidation. The mRNA expression levels of several
proteins associated with inflammation were increased, including
interleukin-1\selectlanguage{greek}β \selectlanguage{english}(IL-1\selectlanguage{greek}β\selectlanguage{english}), IL-6, tumor necrosis factor- \selectlanguage{greek}α \selectlanguage{english}(TNF-\selectlanguage{greek}α\selectlanguage{english}),
mitogen-activated protein kinase 3 (MAPK3), nuclear factor-\selectlanguage{greek}κ\selectlanguage{english}B (NF-\selectlanguage{greek}κ\selectlanguage{english}B,)
and caspase-3. The relative abundance of \emph{Firmicutes}
and\emph{Lactobacillus} species were reduced, while the abundance of
several pathogenic species, mainly Fusobacteria strains, was increased
{[}61{]}. In a study published in 2022, Fusobacteria were found to be
more abundant in the gut of autistic children compared to normal
controls {[}62{]}.

Gluten intolerance is a prevalent feature of autistic children, and many
parents have implemented a gluten-free diet with the hope of healing
their childrens' guts {[}63{]}. A remarkable case study involved a
5-year-old boy diagnosed with severe autism. Diagnosis of underlying
celiac disease motivated implementation of a gluten-free diet along with
various nutritional supplements. The child's gastrointestinal symptoms
rapidly improved, and symptoms of autism abated. The authors suggested a
malabsorption syndrome associated with central nervous system
dysfunction {[}64{]}. Glyphosate is commonly used on wheat crops as a
desiccant just before harvest, and this has resulted in high levels of
glyphosate contamination in wheat-based foods {[}65{]}. Glyphosate usage
on wheat has increased over time, in step with the rise in celiac
disease {[}66{]}.

Glyphosate has been linked to asthma in both human and animal studies. A
study focused on the town of Monte Ma\selectlanguage{ngerman}íz in Córdoba, Argentina examined a
possible relationship between glyphosate and asthma in the population
there. This town was selected because it is situated in the middle of an
agricultural region where glyphosate is heavily used on genetically
modified corn and soy crops. Volatile grain dust from pulverized soy and
corn grain husk is stored in huge silos in the town. Winds can easily
disperse the dust into the surrounding area. Glyphosate and
aminomethylphosphonic acid (AMPA) (a toxic breakdown product of
glyphosate) were detected in 100\% of the soil samples taken near the
silos, and the levels of glyphosate and AMPA far exceeded the levels of
any other pesticides. The asthma rates were significantly higher overall
in the town compared to the rate in Argentina and were highest for those
in close vicinity to the silos. The rate of asthma in the
18--45-year-old population living near the silos was more than double
the national average {[}67{]}. In another study, mothers with asthma
were 62\% more likely to deliver an infant later diagnosed with autism
{[}68{]}.

In a study on farmers in North Carolina and Iowa, glyphosate, the most
commonly used herbicide there, was significantly associated with both
asthma and wheeze, whereas no association was found with the related
herbicide glufosinate {[}69{]}. Exposure of mice to glyphosate-rich air
samples induced IL-13 dependent pulmonary inflammation and induced the
release of Th2 cytokines, a likely mechanism for increased asthma risk
{[}70{]}.

\textbf{Glyphosate and Eosinophilic Esophagitis}

Eosinophilic Esophagitis (EoE) is an emerging chronic immune-mediated
disease that causes damage to the esophagus through excessive fibrosis,
mediated by excessive infiltration of eosinophils into the esophagus and
overexpression of IL-13. It currently affects one in 1000 people in the
United States {[}71{]}. EoE was first identified in 1993, and its rate
has been rising in prevalence over time since then. In an experiment
designed to assess whether glyphosate could be causal in this alarming
rise over time, mice were exposed to physiological levels of glyphosate
in utero and throughout their lifespan. Chronic glyphosate treatment
induced a 2-fold increase in esophageal eosinophils compared to baseline
{[}71{]}.

It is noteworthy that there are several other health conditions that
have been found to co-occur with EoE, and it is likely that these
correlations point to a common cause, namely glyphosate exposure. One of
the strong comorbidities is autism, which is also comorbid with food
allergies and gastrointestinal disturbances that co-occur with EoE. A
study based in Virginia involving 266 children with a diagnosis of EoE
found that 12.7\% of them also had a diagnosis of autism {[}73{]}. This
is much higher than the prevalence in the general population. A study
based in Nevada found strong comorbidities between EoE and several
different conditions, including gastroesophageal reflux disease (GERD)
(3.69\%), diseases of the gut (7.26\%), asthma (13.4\%) and pollen and
food allergies (7\%) {[}74{]}. Adults with autism were found to have a
highly significant increased risk of GERD (p = 0.0001) {[}75{]}. We have
already seen that glyphosate is a risk factor for asthma {[}67{]}.

A study on 56 patients diagnosed with celiac disease found that six of
them (10.7\%) also had a diagnosis of EoE {[}76{]}. It has been
hypothesized that glyphosate may be the primary cause of the rise in
celiac disease in recent decades, which correlated strongly with the
rise in the use of glyphosate on wheat as a desiccant {[}66{]}. Children
with ASD are at a higher risk of gastrointestinal disorders and gluten
intolerance, compared to the general population {[}77{]}.

\textbf{Glyphosate and Glutamate Neuroexcitotoxicity}

Cattani et al. have demonstrated that maternal exposure of pregnant rats
to glyphosate-based herbicide leads to glutamate neuroexcitotoxicity in
the hippocampus of the offspring {[}78{]}. Exposure of pregnant female
Wistar rats to the glyphosate-based herbicide Roundup at the no observed
adverse effect level (NOAEL) for maternal toxicity, during pregnancy and
lactation, led to significant neuroexcitotoxicity effects in the brains
of the pups, due to excess extracellular glutamate {[}78{]}. Roundup
reduced glutamate uptake from the synapse by astrocytes and increased
the release of glutamate into the synaptic cleft by neurons in the
hippocampus. Glyphosate suppressed the enzyme glutamine synthetase in
astrocytes, impairing their ability to safely store glutamate as
glutamine. Glyphosate also reduced the levels of glutathione and
increased the levels of lipid peroxidation products {[}78{]}. Excess
extracellular glutamate disrupts cystine (a cysteine dimer) uptake by
cells via the Cystine/Glutamate Antiporter System xc-. This depletes the
levels of glutathione, since cysteine is the rate-limiting substrate for
glutathione synthesis {[}79{]}.

In another study by Cattani et al., rats chronically exposed to low-dose
glyphosate both prenatally and postnatally exhibited evidence of
glutamate-related neurotoxicity at 60 days of age {[}80{]}. The exposed
rats exhibited oxidative stress markers associated with depressive-like
behavior. Astrocyte activation was suggested by elevated serum levels of
the astrocytic protein S100B, a marker of astrocyte activation. S100B
serum levels have been found to be elevated in association with autism
{[}81{]}. A study on 40 patients suffering from poisoning by either
glyphosate (23) or glufosinate {[}82{]} (17) found statistically
significant correlations between serum levels of S100B and neurological
complications {[}83{]}.

Glyphosate exposure to goldfish (as Roundup) at low levels induced
oxidative stress and suppressed the activities of superoxide dismutase
(SOD), glutathione S-transferase (GST), glutathione reductase, and
glucose-6-phosphate dehydrogenase in the tissues of the fish. SOD
activities were reduced by 51 to 68\% in the brain {[}84{]}. All these
enzymes play important roles in reducing oxidative stress.

A comprehensive review paper with over 200 references detailed the toxic
effects of glyphosate specifically on the nervous system. These authors
wrote: ``The results analyzed herein reflect the capacity of glyphosate
to induce oxidative stress, neuroinflammation, and mitochondrial
dysfunction, processes that lead to neuronal death by autophagia,
necrosis, or apoptosis, as well as the appearance of behavioral and
motor disorders.'' {[}85{]}, p. 27.

\textbf{Does Glyphosate Suppress PIN1 in Neurons?}

DAPK1 is a stress-responsive calcium/calmodulin
(Ca\textsuperscript{2+}/CaM) dependent serine/threonine (Ser/Thr) kinase
and a mediator of pro-apoptotic cell death {[}86{]}. Among its many
other functions, DAPK1 phosphorylates PIN1 on Ser71 in the catalytic
active site. This phosphorylation fully inactivates PIN1 catalytic
activity, as well as inhibiting its nuclear localization. DAPK1 is
upregulated in the brains of patients with Alzheimer's disease, and its
overexpression is implicated in Alzheimer's pathology {[}87{]}.
Melatonin plays a central role in DAPK1 regulation. It binds to DAPK1
and promotes its ubiquitinization, resulting in its clearance through
proteasomal degradation {[}87{]}.

While melatonin is mainly viewed as a molecule that is produced by the
pineal gland in the evening to promote sleep, it is also produced by
many other cell types. In particular, microglia synthesize abundant
melatonin which can transform them from a pro-inflammatory M1 phenotype
to an anti-inflammatory M2 phenotype. Melatonin synthesized by microglia
in the cerebellum shortens the pro-inflammatory phase of activated
microglia {[}88{]}. Melatonin has many beneficial protective effects on
regulatory pathways. It significantly decreases DAPK1 expression in a
post-transcriptional manner in neuronal cell lines and mouse primary
cortical neurons {[}87{]}. Melatonin protects from ferroptosis via the
Akt/NRF2/Gpx4 signaling pathway. The likely mechanism could be its
suppression of DAPK1, which then allows PIN1 activation, and
subsequently NRF2 activation through PIN1 binding, a topic we will
return to later {[}89{]}. While melatonin increases the expression of
NRF2, it also decreases the expression of the inflammatory markers
TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β, \selectlanguage{english}IL-6 and inducible nitric oxide synthase (iNOS) {[}90{]}.

Another way in which PIN1 can become suppressed is through insufficient
levels of the antioxidant glutathione in the cell. When glutathione
becomes depleted, PIN1 becomes oxidized by hydrogen peroxide, and this
inactivates it. The PIN1 active site contains an essential cysteine
residue (Cys113), which is very sensitive to oxidation. Treatment of
PIN1 with hydrogen peroxide results in the oxidation of Cys113 to
sulfinic acid, and this reaction completely disables its isomerase
activity {[}91{]}. This leads to impaired translocation of NRF2 and p53
to the nucleus, which shuts down their activation of a broad spectrum of
enzymes that would normally promote antioxidant defenses and cell
survival, respectively. We will have more to say about this in a later
section.

We shall see in the next section that glyphosate's disturbance of
glutamate signaling in the brain leads to severe deficiencies of
glutathione in neurons.

\textbf{Glutamate Neuroexcitotoxicity and Glutathione Depletion}

Disturbances in the glutamatergic system are a common feature in autism,
with imbalances in both the excitatory and inhibitory networks
{[}92-94{]}. Glutamate is directly involved in brain development and
synaptogenesis, and disrupted glutamatergic signaling is associated not
only with autism, but also with epilepsy, schizophrenia, and depression
{[}95{]}. In one study, children with autism and their family members
had elevated levels of glutamate in the blood, along with reduced levels
of glutamine {[}96{]}.

Methylmercury, arsenic, lead, and paraquat exert a common toxic effect
by inducing oxidative stress, mitochondrial damage, and depletion of
glutathione {[}8{]}. The loss of glutathione is mediated in part through
the accumulation of extracellular glutamate. Glutamate is the most
important excitatory neurotransmitter in the brain, but in excess it
becomes neurotoxic. Excessive activation of glutamate receptors leads to
excessive calcium influx and activates a cell death cascade due to
mitochondrial reactive oxygen species (ROS) {[}97{]}.

A mechanism that results in glial cells releasing nonvesicular glutamate
into the extrasynaptic space is a key factor in pathological glutamate
signaling {[}98{]}. The cystine-glutamate antiporter system, xc- is the
major route by which cysteine is taken up into cells (in its oxidized
form as cystine) {[}97{]}. Extracellular glutamate is a competitive
inhibitor of xc-, preventing uptake of cystine by the cell. Cysteine is
the rate-limiting amino acid for glutathione synthesis. Thus, when
extracellular glutamate accumulates following toxic exposures,
glutathione becomes depleted {[}79{]}. N-acetyl cysteine (NAC) has found
therapeutic value in treating autism, and this is likely due to the
increased bioavailability of cysteine to support glutathione synthesis
{[}99,100{]}.

\textbf{Glyphosate, Diabetes, Melatonin Deficiency and Autism}

Acting as an endocrine disruptor, glyphosate can disrupt insulin
signaling, leading to diabetes. Diabetes prevalence is rising in the
United States in step with the rise in glyphosate usage on core crops
{[}57{]}. Oral exposure of albino Wistar rats to glyphosate for 16 weeks
was associated with a rise in fasting glucose and insulin, along with a
drop in serum testosterone, and an increase in liver production of
pro-inflammatory factors, including NF-\selectlanguage{greek}κ\selectlanguage{english}B, Il-6, Il-1\selectlanguage{greek}β, \selectlanguage{english}and peroxisome
proliferator-activated receptor-\selectlanguage{greek}γ \selectlanguage{english}(PPAR-\selectlanguage{greek}γ\selectlanguage{english}) {[}101{]}. Maternal diabetes
during pregnancy is associated with increased risks for autism spectrum
disorder and cognitive dysfunction in the offspring {[}102{]}. High
circulating glucose levels interfere with pineal melatonin production,
reducing melatonin levels in diabetic rats and type 1 diabetes patients
{[}103{]}. Type 2 diabetic Goto-Kakizaki rats exhibit impaired melatonin
synthesis, with increased inhibitory \selectlanguage{greek}α-\selectlanguage{english}2-adrenoceptors, impaired
5-hydroxytryptophan formation, and reduced pineal gland protein content
{[}104{]}. Thus, impaired melatonin supply to the fetus during pregnancy
due to maternal diabetes could cause autism in the developing fetus via
suppression of PIN1 signaling by DAPK1.

\textbf{A Proposed Role for Glyphosate in Shared Pathway Disruptions in
Autism, Alzheimer's Disease and Cancer}

Perhaps surprisingly, autism and Alzheimer's disease overlap
considerably in symptoms, genetics, and mechanisms, suggesting a similar
underlying pathology {[}105{]}. PIN1 is normally expressed at very high
levels in neurons, but it is inhibited in neurons in Alzheimer's disease
via multiple mechanisms, including downregulation, oxidation,
phosphorylation and sequestration {[}106{]}. Just as autism rates over
time are highly correlated with glyphosate usage on core crops,
age-adjusted deaths due to Alzheimer's disease over time had a
correlation coefficient R of 0.917 with glyphosate usage on corn and soy
crops in the United States, with a p-value of 2.2E-7 for the probability
of a chance occurrence {[}57{]}.

Also surprisingly, autism and cancer share common features involving
mitochondrial dysfunction and dysregulated metabolic pathways, including
p53, AKT, mTOR, WNT, NOTCH, and MAPK {[}107{]}. There is considerable
overlap in the risk genes linked to both conditions {[}108{]}.
Dysregulated ERK/MAPK signaling can lead to mitochondrial dysfunction
upon toxic exposures in both neurons and tumor cells {[}109{]}. PIN1
overexpression is a well-known feature of tumor cells, where it
facilitates mitosis, proliferation, and metastasis {[}110{]}.

By contrast, we argue here that PIN1 is suppressed in neurons in
association with autism, as is the case for many neurodegenerative
diseases, especially Alzheimer's {[}111,112{]}. A neuron is a fully
differentiated cell type that is intricately connected to large networks
of other neurons. They do not have the option of dividing in the face of
stressors. As a consequence, upon toxic exposures, their regulatory
pathways have an opposite effect on PIN1 compared to cancer cells, and
this drives them toward apoptotic signalling rather than inducing
cellular proliferation following severe DNA damage. Oxidative stress can
cause severe DNA damage {[}113{]}. Much of what is known about PIN1's
function in cells was discovered through studies on cancer cells. In
future sections we will reference this literature to help explain the
many roles of PIN1 in biology.

\textbf{Overexpressed mTOR Signaling Pathway:} Autism is associated with
increased dendritic spine density and reduced developmental spine
pruning in neurons. These defects are correlated with overexpressed mTOR
signaling and impaired autophagy. This potential for autophagy
impairment would result in serious interference in the associated cell
death mechanisms that can consequently lead to development of disease
{[}114{]}. Designer mice have been created with constitutively expressed
mTOR activity due to a defect in gene expression of proteins that
inhibit mTOR. These mice exhibit autistic behaviors and have the same
characteristic spine pruning defects in pyramidal neurons in the
temporal lobe, along with impaired autophagy {[}115{]}. Microglia play
an important role in synaptic pruning, as mice with deficient autophagy
in microglia are impaired in synaptic pruning and exhibit behaviors
characteristic of autism {[}116{]}.

\selectlanguage{greek}\textbf{Wnt/β-catenin Signaling Pathway:}\selectlanguage{english} Several of the genes
associated with autism converge in the regulation of the Wnt/\selectlanguage{greek}β-\selectlanguage{english}catenin
signaling pathway. Both gain and loss of function in this pathway
contribute to abnormalities in embryonic brain development associated
with autism {[}117{]}. Cultivated neurons exposed to glyphosate were
impaired in differentiation and growth, eliciting shorter and unbranched
axons, and developing less complex dendritic arbors compared to controls
{[}118{]}. These features are characteristic of impaired neuronal
maturation in autism {[}119{]}. In the glyphosate study, it was found
that both the expression of Wnt5a and the activity of the
serine/threonine kinase CaMKII were decreased {[}118{]}.
Autophosphorylation of CaMKII increases its activity and prolongs the
duration of its active state. A missense mutation in CaMKII that results
in impaired autophosphorylation and more rapid turnover is associated
with autism. When this mutation was introduced in mice, they displayed
autistic-like behaviors {[}120{]}. Rat pups exposed to glyphosate in
utero showed inhibition of the Wnt5a-CaMKII signaling pathway,
associated with defects in motor activity and cognitive function
{[}121{]}.

The corpus callosum is the largest white matter tract in the brain, and
it connects the two cerebral hemispheres together. Wnt5a-evoked CaMKII
signaling instructs specific growth and guidance behaviors in the corpus
callosum, controlling its development {[}122{]}. Intriguingly, the
corpus callosum is thin and underdeveloped in PIN1 knockout mice
{[}123{]}. Many neurodevelopmental disorders have been linked to
malformation of the corpus callosum, including autism, ADHD, and
schizophrenia {[}124{]}. BTBR mice, a well-established model for mouse
autism, exhibit complete agenesis of the corpus callosum {[}125{]}. A
large percentage of humans suffering from agenesis of the corpus
callosum display many traits associated with autism, including deficits
in communication and social skills and repetitive behaviors {[}126{]}.

The DAPK1 regulatory function, which inhibits PIN1 activity, is central
to CaMKII autophosphorylation of threonine at position 286 (Thr286),
which is required for synaptic long-term potentiation (LTP) and
depression (LTD) {[}127,128{]}. Both LTP and LTD, which oppose each
other, are involved in synaptic plasticity. The autophosphorylation of
CaMKII results in the binding of the molecule to the
N-methyl-D-aspartate (NMDA) receptor (NMDAR) subunit GluN2B and
accumulation of CaMKII during LTP. DAPK1, through activating calcineurin
(CaN), blocks CaMKII from binding to GluN2B by competitive inhibition.
This creates a fine balance, regulated by Ca2+/CaM influx, which
determines whether CaMKII will become attached to GluN2B (establishing
LTP), or not (establishing LTD), a balance that is deregulated in
autism. Specifically, DAPK1 overexpression, which we have argued can
happen due to glyphosate's inhibition of melatonin synthesis, inhibits
the accumulation of CaMKII in the synapse following LTP stimuli
{[}128{]}.

Wnt/\selectlanguage{greek}β-\selectlanguage{english}catenin signaling increases both mRNA expression and protein
synthesis of the cell adhesion molecule neuroligin-3, which in turn is
essential for the maturation of synapses. Genetic mutations in
neuroligin-3 are associated with autism {[}129{]}. \selectlanguage{greek}β-\selectlanguage{english}catenin is a major
substrate for PIN1 in neural progenitor cells. The developing brain of
PIN1 knockout mice shows reduced expression of \selectlanguage{greek}β-\selectlanguage{english}catenin during
differentiation, leading to significantly fewer upper layer neurons in
the motor cortex {[}130{]}.

\selectlanguage{greek}\textbf{The Integrin β1/FAK/SRC Signaling Pathway:}\selectlanguage{english} Tetraspanin 7
(TSPAN7) is a master regulator of morphological changes that take place
during cell differentiation through cytoskeleton remodeling {[}131{]}.
Focal adhesion kinase (FAK) is a tyrosine kinase that regulates cellular
adhesion, motility, proliferation, and survival, and it interacts with
TSPAN7 through the Integrin \selectlanguage{greek}β\selectlanguage{english}1/FAK/SRC signaling pathway. FAK plays an
important role in neural migration, dendritic morphology, axonal
branching, and synapse formation, all of which are dysregulated in
autism {[}132{]}. Activation and autophosphorylation of FAK promote
neurite formation in neurons {[}133{]}. TSPAN7 knockout rats exhibit
autism-like behaviors, and this has been linked to impairments in this
pathway, which is critical for neurite outgrowth {[}134{]}.

One of the major pathogenic features of autism is reduced cell
migration. Lymphoblasts share features with neurons, and it has been
discovered that growing them in culture can serve a useful role to
identify systemic pathologies in pathways linked to specific diseases.
The protein expression level of FAK is significantly decreased in
autistic lymphoblasts, and this was associated with increased adhesion
properties and decreased migration, attributed to impaired FAK function
in the lymphoblasts {[}132{]}. PIN1 isomerizes two prolines in FAK
adjacent to Ser-910 and Ser-571, and this leads to dephosphorylation of
FAK Tyr-397 {[}110{]}. PIN1 isomerization is required to recruit the
phosphatase to FAK. Dephosphorylation of FAK at Tyr397 inhibits FAK
kinase activity, promoting the disassembly of focal adhesion and
enhancing tumor cell metastasis {[}135{]}. Experimentally, FAK Tyr-397
dephosphorylation causes cells to round up and lose their attachment to
focal adhesions, promoting cellular migration {[}136{]}. Thus, low
expression of PIN1 would explain the pathology observed in autism,
because it leads to suppression of FAK Tyr-397 dephosphorylation.
Autistic neurons have reduced migratory capabilities due to increased
adhesion complexes that lead to migratory defects, a process in which
PIN1 inactivation and DAPK1 over-activation are major participators.
This defect interferes with the maturation process of neurons in the
brain during neurodevelopment.

\textbf{Glyphosate, FAK and Anoikis}

The motif Arginine-Glycine-Aspartate (RGD), expressed in integrin
ligands, is the recognition site for integrin binding to these ligands,
and it regulates cell-cell and cell-extracellular matrix (ECM)
interactions. Short synthetic peptides that contain the RGD sequence
promote cell adhesion when adhered onto a surface, by binding to
integrins in the cell membrane, and inhibit it through a decoy
phenomenon when presented to cells in solution {[}137{]}. It has been
proposed and demonstrated experimentally that glyphosate has biomimetic
features that cause it to disrupt cellular adhesion properties in
unpredictable ways. Glyphosate can mimic an RGD binding site, and, as a
consequence, glyphosate adsorbed on the surface of a cell enhances
cellular adhesion. By contrast, glyphosate in solution can act as a
decoy to interfere with focal adhesion. These authors hypothesized that
the interference of glyphosate in solution with cellular adhesion
processes could trigger anoikis {[}138{]}. Anoikis (``homelessness'' in
Greek) is a form of apoptosis that is induced by disrupted cell--ECM
interactions {[}139{]}.

Inappropriate cell-substrate contact triggers anoikis {[}140{]}. FAK
gene silencing has been shown to promote anoikis in adenocarcinoma cells
{[}140{]}. This is consistent with the idea that neuronal cell death by
anoikis would be a feature of autism, given that FAK signaling is
reduced in association with autism {[}134{]}. Thus, downregulation of
FAK/SRC signaling in autism due to decreased FAK activity is expected to
lead to enhanced apoptosis by anoikis in the brains of autistic
individuals {[}132,141{]}.

\textbf{PIN1, PSD-95, the Synapse, and Glyphosate}

Postsynaptic density protein-95 (PSD-95) is a major regulator of
synaptic maturation. It interacts with NMDA receptors and
\selectlanguage{greek}α-\selectlanguage{english}amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors,
stabilizing and trafficking them to the postsynaptic membrane. PSD-95 is
involved in glutamatergic transmission, synaptic plasticity, and
dendritic spine morphogenesis during neurodevelopment. PSD-95 null mice
have learning and memory deficits and impaired socialization, associated
with increased NMDAR expression {[}142{]}. There is now overwhelming
evidence that PSD-95 disruption is associated with the cognitive and
learning deficits that are characteristic of autism and schizophrenia
{[}143,144{]}.

Glyphosate exposure in rats has been shown to affect synaptic function.
Studies have demonstrated that glyphosate exposure leads to a decrease
in dendritic complexity, synaptic spine formation and maturation, and
synapse formation in hippocampal neurons. Glyphosate downregulates the
expression of synaptic proteins such as synapsin-1, PSD-95, and CaMKII,
and decreases PSD-95 clustering in the hippocampus. These changes in
synaptic assembly and protein expression likely contribute to the
impairment of cognitive function and neuronal connectivity in rats
exposed to glyphosate {[}145{]}.

PSD-95 is a membrane-associated guanylate kinase, and it is the main
scaffolding protein at excitatory postsynaptic densities (PSDs). It
plays a major role in regulating synaptic strength and plasticity.
PSD-95 anchors NMDA receptors (NMDARs) in the PSD, thus increasing their
numbers. Phosphorylated PSD-95 recruits PIN1 to the synapse, and PIN1
controls the synaptic content of NMDARs via PSD-95 prolyl-isomerization.
PSD-95 has six potential PIN1 consensus motifs between the PDZ2 and PDZ3
domains, and binding of PIN1 following phosphorylation of the preceding
serine/threonine greatly influences its behavior {[}146{]}.

Specifically, prolyl-isomerization following phosphorylation decreases
the ability of PSD-95 to complex with NMDARs, leading to a
downregulation of NMDAR-mediated synaptic transmission, and this is
associated with a decrease in dendritic spine density. Thus, PIN1
deficiency would be expected to result in \emph{upregulated} NMDAR
expression and \emph{increased} dendritic spine density. Indeed, PIN1
null mice have an increase in spine density {[}146{]}, a feature that is
commonly associated with autism {[}147{]}. Upregulation of NMDARs at
neuronal synapses, along with increased glutamine synthetase expression
in astrocytes, has been linked to autism in a mouse model {[}148{]}.
NMDAR expression was upregulated in the brain in another mouse model of
autism, and the NMDAR antagonist memantine was used to treat their
autistic-like behaviors {[}149{]}. Memantine has also been proposed to
have therapeutic value to treat autism in humans {[}150{]}.

The term synaptopathy is used to describe brain disorders associated
with synaptic dysfunction. \emph{DLG4} is the gene that encodes
PSD-95.\emph{DLG4} -related synaptopathy refers to a group of
neurodevelopmental disorders associated with variants in the \emph{DLG4}
gene. Many of the variants are de novo loss-of-function mutations, which
may disrupt binding to PIN1. These disorders are characterized by a
broad range of symptoms including global developmental delay,
intellectual disability, autism spectrum disorder, attention
deficit-hyperactivity disorder, and synaptic dysfunction {[}151{]}.

\textbf{DAPK1's role in apoptosis and the related molecular regulations
of cancer pathways and neuronal damage}

DAPK1 is among the proteins positively regulating cell death by
apoptosis and thus working to prevent cancer metastases. We have already
seen that glyphosate suppresses melatonin synthesis, and that melatonin
plays a critical role in suppressing DAPK1 activity {[}39,87{]}. DAPK1
is a potent modulator of PIN1 activity and their molecular interactions
are significantly implicated in the development of tau-associated
pathology {[}104{]}, in the amyloid \selectlanguage{greek}β-\selectlanguage{english}related pathology of Alzheimer's
disease (AD) {[}152{]} and in the disablement of neuronal network
restoration following neural traumas {[}153{]}. Therefore, as DAPK1
directly inhibits PIN1 function {[}86{]}, it is important to revisit
DAPK1 regulatory aspects of activation and/or deactivation that relate
to the DAPK1 tertiary structure. These regulatory activities affect the
molecular activity of PIN1 and other important molecules implicated in
neurodegeneration and cancer.

DAPK1 has a multi-domain structural organization that enables it to
perform a wide range of functions, succinctly described in a study by P
Singh et al. {[}86{]}. What is outstanding about this molecule, and a
feature that differentiates it from other kinases, is that DAPK1 does
not require an extra phosphorylation event in its catalytic domain to
become activated. Near the DAPK1 catalytic kinase domain, there is an
autoregulatory Ca\textsuperscript{2+}/CaM domain that serves as a
pseudo-substrate for the catalytic domain, and when CaM is not bound to
that region, the function of DAPK1 is auto-inhibited. It is for this
reason that the catalytic domain of DAPK1 is unique compared to other
kinases.

Adjacent to the peptide-to-peptide region in the catalytic domain, there
is a protruding positively charged comb region that allows for numerous
regulatory properties of DAPK1, including the regulation of apoptosis
{[}154{]}. However, it is the extra-catalytic domain molecular
interactions that are important for DAPK1's activity, degradation and
cellular localization. Next to the CaM autoregulatory domain (which
inhibits the catalytic domain of DAPK1 in the absence of CaM), lies an
ankyrin repeat rich domain, which is responsible for many of the
protein's interactions. This ankyrin repeat rich domain determines
DAPK1's ubiquitination status and subsequent proteasomal degradation.

\textbf{DAPK1, Anoikis and Synapses:} In the absence of the ankyrin
repeats, DAPK1 localizes from actin filaments to focal adhesions, and
this relates to tropomyosin regulation by DAPK1 phosphorylation and
facilitation of cancer cell death. This function of DAPK1 is very
important as it regulates the phenomenon called anoikis that prevents
cancer. Anoikis is a distinct cell-death process similar to apoptosis,
and it reflects the capacity that normal cells have to migrate and stay
alive; whereas, when DAPK1 is activated in cancer cells that attach to
soft surfaces, anoikis is initiated and these cells die, thus
restricting their migration and metastatic potential {[}155,156{]}.
Anoikis is a safeguard mechanism that lets healthy cells remain alive
and functional, whereas it kills abnormal neural cells that have
pathological adherence junctions during embryonic development.

DAPK1's ankyrin repeat sequence is essential for its protein-to-protein
communication, as is the case for many other ankyrin repeat proteins
{[}157{]}. For DAPK1, the ankyrin repeat domain mainly functions to
provide control of its amounts in cells, regulated via ubiquitination
and proteasomal degradation of the protein {[}158{]}. The DAPK1 ankyrin
repeats react strongly with DAPK interacting protein-1 (DIP-1),
targeting the proteasomal degradation of DAPK1. Thus, whether or not
DAPK1 will exert apoptosis survival signaling in normal cells depends on
the expression and interactions of its ankyrin repeat domain with DIP-1.
When DIP-1 is expressed, it forms a strong complex with DAPK1 and DAPK1
suffers from DIP-1's ubiquitination in the complex and it is thereby
tagged for proteasomal degradation {[}158{]}. However, when the DAPK1
ankyrin repeat domain is deleted, DAPK1 relocalizes from actin
cytoskeleton microfilaments to adhesion complexes where it exerts cell
death by anoikis of migrating cancer cells {[}156{]}.

DAPK1 is strongly involved in neuronal cell death and the development of
neurodegeneration {[}159{]}. Furthermore, anoikis is considered as a key
pathogenic factor for glaucoma, Alzheimer's disease (AD), amyotrophic
lateral sclerosis (ALS) and Parkinson's disease (PD) {[}160,161{]}.
Therefore, whether the anoikis mechanism of cell death will appear in a
certain type of cell ultimately depends on the functionality of the
ankyrin repeat domain of DAPK1.

Although research on the relationship between anoikis and prion disease
is sparse, there is growing evidence for a role for anoikis in prion
disease pathogenesis. The prion protein modulates epithelial to
mesenchymal cell transition {[}162{]}, and anoikis crosstalk with
epithelial-mesenchymal transition in resisting cancer metastasis is
substantial {[}163{]}. Moreover, the prion protein is upregulated in
many cancers {[}164{]}. Therefore, a potential DAPK1 upregulation and
re-localization from microfilaments to adhesion complexes may underly
both neurodegenerative and prion disease pathology.

Figure 1 provides a graphical representation of these complex processes
relating disturbed expression of PIN1 and DAPK1 to disease.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=1.00\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

\textbf{Figure 1: PIN1 deactivation/DAPK1 activation.} When DAPK1
deactivates PIN1 and loses function of its ankyrin repeat domain (ARD),
it travels from the cytoskeleton to focal adhesion complexes. Through
this sub-localization of DAPK1, Src normally catalyzes its
phosphorylation for focal complex assembly to occur. In autism, due to
low expression of FAK and loss of PIN1 activation, Src function
predominates to assembly of matrix adhesion catalysis and impairs
cellular migration. Reduced cellular migration is an impairment
regularly seen in autism. Furthermore, increased cell adhesion complex
assembly contributes to normal cell adhesion and migration and cancer
cell death. On the other hand, anoikis initiated by DAPK1 localisation
to focal adhesion complexes is a causative factor for neurodegenerative
disease pathogenesis and a probable contributing factor for prion
disease and autism\textbf{.}

Preservation of homeostasis in adhesion complex formation has a
significant role in the prevention of neurodegeneration, as it maintains
the normal functions of neuronal synapses {[}165{]}. On a molecular
level, normal synaptic behavior is attributed to synaptic cell adhesion
molecule (CAM) pathways where the scaffolding SH3 ankyrin repeat domain
3 (SHANK3) proteins are the protagonists {[}166{]}. Dysregulation in
these CAM pathways involving neuroligins and neurexins, that regulate
cellular adhesions of synapses, are associated with the pathology of
autism spectrum disorders (ASDs) {[}167{]}. Multiple studies have shown
that many of the genes that are mutated in association with autism
involve proteins that play a critical role in cellular pathways
associated with the synapse. These genes encode scaffolding proteins,
adhesion molecules, and proteins involved in synaptic transmission and
plasticity. This observation has suggested that synaptic dysfunction may
be a core feature of autism {[}168{]}. DAPK1 is highly enriched in the
synaptic dendritic spines, where it plays an important regulatory role
in synaptic plasticity {[}169{]}. Furthermore, PIN1 localizes at
postsynaptic sites and, in particular, at the lipid rafts of dendrites
and postsynaptic density (PSD) areas which cohere to the postsynaptic
membrane and maintain synaptic plasticity {[}170,171{]}.

The loss of PIN1 activity, as found in the brain cortical tissues of AD
patients, results in a decrease in SHANK protein levels and the
alteration of ubiquitin-related modifications of PSD proteins.
Structural abnormalities of the synapses of AD patients are a
consequence. Moreover, the loss of PIN1 activity due to oxidative stress
makes neurons more susceptible to the toxicity of
amyloid-\selectlanguage{greek}\emph{β}\selectlanguage{english}fibrils, and this results in the inhibition of NMDA
receptor stimulation (and therefore reduced synaptic plasticity), as
well as enhancement of NMDA associated degeneration of synapses
{[}171{]}. Constitutionally, the loss of PIN1 activity and a concurrent
operational activity of DAPK1 localised also at synaptic adhesion
complexes of glutamate NMDA receptors would provide a deregulated
response of the otherwise naturally occurring neuronal cell death by
apoptosis {[}172{]}. In cases where the extracellular matrix and the
adhesion of cells fail to be properly regulated, anoikis-induced cell
death, including for neurons, occurs {[}173{]}. These mechanisms can
feasibly explain many of the abnormal neural plasticity features
encountered in autistic individuals {[}168,173{]}.

\textbf{DAPK1 Regulatory Mechanisms and Protein Interactions:} DAPK1 has
a profoundly complex regulatory mechanism involving phosphorylation and
dephosphorylation, and it interacts with many other important proteins
to alter their function in various ways. These other proteins include
not only PIN1, but also many biologically important proteins whose
disruption is linked to autism, including PP2A {[}174{]}, ERK//MAPK
{[}175,176{]}, and p53 {[}177{]}, among others. One of the final
determinants of whether DAPK1 will be activated or not relies on the
phosphorylation of the serine 308 residue, which is located in the Ras
of complex (ROC) protein domain of the molecule, adjacent to the ankyrin
repeat domain. The ROC domain modulates its kinase activity. ROC is a
conserved domain of the ROCO multidomain family of proteins, making
DAPK1 a member of this family. ROC domains are implicated in the
development of neurodegenerative diseases, including Alzheimer's disease
(AD) {[}178{]}. When the ROC domain of DAPK1 interacts with a GTPase,
the subsequent conversion of GTP to GDP phosphorylates Ser-308 and
inactivates the protein {[}86,177{]}. Nevertheless, this makes the
activation of DAPK1 subject to other ROCO protein kinase activations and
regulations {[}178{]}. In contrast, when the same Ser-308 becomes
dephosphorylated by the activity of protein phosphatase 2A (PP2A), an
important protein for cell signaling and growth mostly characterized as
a tumor suppressor, DAPK1 becomes activated {[}86,178,179{]} The
PP2A-DAPK1 interaction and activation via Ser-308 dephosphorylation in
the ROC subdomain is essential for many DAPK1 functions, including
apoptosis, regulation of autophagy and cellular proliferation and
development, and these are especially important cellular events for
halting cancer progression {[}180{]}.

The ROC amino acid sequence of DAPK1, starting from residue 667, is
directly followed by the C terminal of ROC (COR) subdomain consisting of
the ROC-COR domain of DAPK1. This domain is then followed by the Death
Domain (DD), which is highly important for the molecule's functions
{[}86{]}. The ROC-COR and DD domains of DAPK1 are highly significant for
regulation of PIN1 activity {[}181{]}. The 637--1423 sequence of DAPK1
efficiently binds to PIN1. This suggests that the DAPK1
cytoskeleton-binding domain, ranging from 637--847, which involves the
ROC subdomain, is highly likely involved with the binding of PIN1.

The peptide-to-peptide interactions between DAPK1 and PIN1 cause the
de-activation of PIN1's isomerase activity by direct phosphorylation of
Ser71 in Pin1. Although, at first glance the phosphorylation of Ser71
seems to be a phenomenally minor molecular event, its biological and
medical consequences are of high impact for the survival of the cell
{[}86,180,181{]}. The destabilization and thus inhibition of cyclin D1
by DAPK1 is mediated by an additional functional insufficiency of PIN1.
The relevant experiments by TH Lee et al. are ominous {[}181{]}. When
DAPK1 is expressed in its wild form, PIN1 deactivation causes a cyclin
D1 destabilization and reduction in Cyclin D1 promoter activation.
Incapacitation of Cyclin D1 in the cells relates to severe deregulation
of cell cycle progression, amplification of cancerous molecular events
during cell cycling {[}182{]}, and moreover, to the insufficiency of
neural cell proliferation and control that leads to autism {[}183{]}.
Cyclin D1 levels are significantly reduced in various tissues of PIN1
NULL mice {[}184{]}.

Furthermore, the ankyrin repeat, the ROC-COR and the DD domains of DAPK1
are subject to other molecular modifications that influence the
molecule's pluripotent functions. When the tyrosine at positions 491/492
of the ankyrin repeat domain of DAPK1 is phosphorylated by the
proto-oncogene tyrosine-protein kinase Src (from sarcoma), this
deactivates DAPK1 from performing essential anti-cancer intra-molecular
interactions. The Src mediated deactivation of DAPK1 produces a crucial
loss of DAPK1-induced anti-cellular migration and proliferation
functions, and it is surely not coincidental that DAPK1 inactivation by
Src is found in situations of tumor metastasis and progression
{[}185{]}.

However, as described above, DAPK1 over-activation and therefore PIN1
deactivation may be leading factors that contribute to autism brain
pathology by enhanced anoikis (apoptosis) events. FAK plays an essential
role in neuronal migration, neurite growth, pruning, and synapse
formation in the developing brain {[}186,187{]}. It has been proposed
that pathological detachment of progenitor cells during neurogenesis
induces anoikis as a defense mechanism to protect from teratogenic
insults {[}188{]}. This aligns with the observation that both glyphosate
and glyphosate-based herbicides produce teratogenic effects on Xenopus
laevis embryos and chicken embryos {[}189{]}. Plausibly, autistic
neurons, by having a reduced activity of FAK and therefore FAK/SRC
signaling, are defective in their migratory properties and therefore are
prone to enhanced cell death by anoikis during embryonic development.

Another major molecular event for DAPK1 is the phosphorylation of Ser735
located in the ROC-COR domain and the subsequent molecular interactions
with extracellular signal regulated kinase (ERK). The DAPK1 docking
sequence that serves as a substrate for ERK lies within the DAPK1 DD
{[}190{]}. The simultaneous induction of DAPK1 catalytic activity via
the activation of ERK promotes cellular death mechanisms including
neuronal apoptosis {[}191{]}. Moreover, interacting DAPK1 and ERK
mechanisms are involved in malignancy development and autism {[}108{]}.
Finally, the DD of DAPK1 has a strong influence towards cancer
progression, as it is a direct modulator of p53 and a potent stimulator
of the TNF-\selectlanguage{greek}α/\selectlanguage{english}Fas pathway resulting in apoptosis {[}159{]}. DAPK1
phosphorylates p53 at Ser23 by direct binding of DD at the p53 DNA
binding domain. Phosphorylation of p53 Ser23 by DAPK1 induces the
transcriptional activation of BAX, whereas in the cytoplasm it induces
mitochondrial associated necrosis and apoptosis, as indicated in studies
on neurons {[}191-194{]}. Moreover, an indirect regulation of p53 by
DAPK1 is through DAPK1's direct binding to MDM2 and its phosphorylation
at Thr-419. This phosphorylation promotes MDM2 ubiquitination and
proteasomal degradation, liberates p53 from MDM2, and promotes p53
expression. The antitumorigenic associations of MDM2 downregulation and
indirect upregulation of p53 by DAPK1 are of considerable contemporary
interest in breast cancer research {[}195{]}.

\textbf{PIN1's Crucial Role for P53 Expression and Activation}

The tumor suppressor p53 and the proto-oncogene Bcl-2 were two of the
earliest identified cancer-related genes {[}195{]}. p53 is a global
transcription factor that maintains the integrity of the cell under
stressful conditions through its activation of expression of many
proteins involving cell cycle arrest and DNA repair as part of the DNA
stress response. p53 in the cytoplasm also plays an important role in
safeguarding the mitochondria from DNA damage {[}196{]}. PIN1 deficiency
results in defective p53 transactivation {[}197,198{]}, and p53
transactivation is reduced in association with autism {[}199{]}.
Knocking down of p53 in mice significantly promotes repetitive behavior
and reduces sociability, clear signs of autism {[}177,197{]}.

In addition to its role in DNA protection from toxic exposures, p53 is
important in hippocampal neurons for learning and memory. Lee et al.
wrote in their abstract: ``Altogether, our study suggests p53 as an
activity-dependent transcription factor that mediates the surface
expression of AMPAR, permits hippocampal synaptic plasticity, represses
autism-like behavior, and promotes hippocampus-dependent learning and
memory'' {[}177{]}. A study published in 2023 demonstrated that
glyphosate activates microglia via toll-like 4 receptor (TLR4) and
triggers cellular stress, resulting in impaired hippocampal plasticity
and learning {[}200{]}.

Under quiescent conditions, p53 remains bound to MDM2, an E3 ubiquitin
ligase that promotes its constant proteasomal degradation, maintaining
the protein at low levels. Upon stress activation, p53's localization to
the nucleus depends upon binding to PIN1. Genotoxic exposures induce the
phosphorylation and activation of p53 on its Ser/Thr-Pro motifs, and
this allows PIN1 to isomerize critical proline residues in p53. PIN1 in
turn stimulates the DNA-binding activity and transactivation functions
of p53. PIN1-deficient cells are defective in p53 activation, and this
results in impaired checkpoint control in response to DNA damage
{[}198{]}.

Lack of PIN1 also leads to increased destabilization of p53 by its
inhibitor, MDM2. Thr81-Pro82 is a crucial site for PIN1 to promote
checkpoint kinase 2- (Chk2)-dependent phosphorylation of p53 on Ser20.
This serine phosphorylation modification stimulates the dissociation of
p53 from MDM2, protecting it from ubiquitination and degradation
{[}198,201{]}.

p53 still induces cell death when it is impaired in its ability to
localize to the nucleus. When PIN1 levels are low under stressful
conditions, p53 accumulates in the cytoplasm, where it can induce death
by apoptosis or necrosis {[}202,203{]}. p53 interacts in the cytoplasm
with Bcl-2, the founding member of the Bcl-2 family of proteins that
regulate cell death, to suppress its anti-apoptotic activity, thus
sensitizing the cell to apoptosis via permeabilization of mitochondria
{[}195{]}. This extranuclear influence of p53 has been coined as
transcription-independent p53-induced apoptosis (TIPA) {[}204{]}. p53
can also inhibit cystine uptake, leading to ferroptosis due to
glutathione depletion {[}205{]}. Cytoplasmic, but not nuclear, p53
suppresses macroautophagy, through activation of the mTOR pathway
{[}206,207{]}. We will return to this topic in a later section since it
pertains to autism.

Palmitate is the most common saturated fatty acid in food, but it can
lead to lipotoxicity and apoptosis in exposed cells. p53 provides some
protection against palmitate-induced apoptosis through its activation of
gene expression of DNA-protective proteins. However, this depends upon
its ability to translocate to the nucleus, which in turn depends upon
PIN1. Experimentally, cell lines from p53-/- mice were significantly
more sensitive to apoptosis through excessive ROS in response to excess
palmitate exposure {[}208{]}.

\textbf{PIN1's Crucial Role in NRF2 Expression and Activation}

Nuclear factor erythroid 2-related factor 2 (NRF2) is a transcription
factor that plays a crucial role in cellular defense mechanisms,
particularly in response to oxidative stress, by transactivating a large
number of genes associated with the stress response, including
antioxidant, anti-inflammatory, and detoxification proteins {[}209{]}.
NRF2 activation leads to increased synthesis of the potent antioxidant
glutathione. The activation of NRF2 typically involves its translocation
to the nucleus, where it binds to antioxidant response elements (AREs)
in the promoters of target genes, initiating their transcription
{[}210{]}.

In a review study published in 2021, collectively involving 87 studies
with 4928 children with autism and 4181 controls, it was reported that
the levels of reduced glutathione, total glutathione, methionine,
cysteine, folate, vitamin D and cobalamin were consistently
significantly reduced in children with ASD compared to the controls
{[}211{]}. In a post-mortem study, glutathione synthase expression was
significantly decreased in frontal cortex brain tissue from seven autism
subjects compared to 8 controls. NRF2 gene expression was also decreased
in the frontal cortex, and this downregulation corresponded to a
decrease in the abundance of methylcobalamin and total cobalamin, as
well as S-adenosylmethionine (SAMe) {[}212{]}.

Kelch-like ECH-associated protein 1 (KEAP1) is a ubiquitin ligase that
senses oxidative stress and tightly regulates the activity of NRF2.
Under normoxic conditions, NRF2 is bound to KEAP1, and this binding
keeps it in the cytoplasm and prevents it from entering the nucleus.
Also, intracellular levels of NRF2 are kept low because proteasomal
degradation (ubiquitination) of NRF2 persists when it is tied up in a
KEAP1/NRF2 complex {[}213{]}. However, under elevated intracellular
levels of ROS, the cysteine residues of KEAP1 sensor domains become
oxidized, and this triggers conformational alterations of the KEAP1
tertiary structure, which results in the release of NRF2 from the
protein complex. This renders NRF2 free to enter the nucleus and proceed
with its antioxidant and cytoprotective activities by inducing the
expression of the NRF2-ARE related gene targets {[}214{]}.

Paradoxically, acute oxidative stress can suppress NRF2 protein
synthesis, through the global inhibition of protein synthesis {[}215{]}.
Supraphysiologic levels of stress can even induce misfolding of both
KEAP1 and NRF2, a maladaptive event that impairs protein function.
Treatment of both yeast and mammalian cells with hydrogen peroxide
results in the formation of misfolded protein inclusions, dose
dependently {[}214{]}.

PIN1 stabilizes NRF2 by competing with KEAP1 for NRF2 binding {[}216{]}.
Furthermore, the common heat shock protein HSP90\selectlanguage{greek}α \selectlanguage{english}is a molecular
chaperone that is essential for transport of NRF2 to the nucleus, but
this also critically depends on PIN1. Prolyl isomerization of NRF2 by
PIN1 allows importin \selectlanguage{greek}α\selectlanguage{english}5 to associate with the Hsp90\selectlanguage{greek}α-\selectlanguage{english}PIN1-NRF2 complex.
A dynein motor system transports this complex along microtubules toward
the nuclear pore complex, achieving the import of NRF2 into the nucleus,
as illustrated in Figure 2 {[}217{]}. The BTBR (Black and Tan BRachyury)
mouse strain is a commonly used mouse model of autism {[}218{]}.
Sulforaphane is a natural molecule derived from cruciferous vegetables,
and it has been shown to activate NRF2 {[}219{]}. BTBR mice treated with
sulforaphane had reduced repetitive behaviors and improved
socialization. Glutathione peroxidase and glutathione reductase activity
were increased in both the periphery and the brain of these mice.
Oxidative stress parameters such as the NF-\selectlanguage{greek}κ\selectlanguage{english}B transcription factor and
lipid peroxides were reduced in their neutrophils {[}220{]}. This
implies that impaired NRF2 transactivation due to insufficient PIN1 is a
feature of autism.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.98\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

\textbf{Figure 2: NRF2-PIN1 interaction.} NRF2 remains inactive in the
cytoplasm under stress-free conditions, bound to KEAP1. Under conditions
of oxidative stress, PIN1 plays an essential role in the activation of
NRF2. Upon NRF2 stabilization by PIN1, it can influence cellular policy
in two distinct ways, depending on its localization in the cell.
Interaction with the dynein motor complex and HSP90\selectlanguage{greek}α \selectlanguage{english}localizes the
complex to the actin cell cortex. On the other hand, when the NRF2/PIN1
complex interacts with importin \selectlanguage{greek}α\selectlanguage{english}5 and importin \selectlanguage{greek}β\selectlanguage{english}1, it enters the
nucleus via the nuclear pore complex, and activates many genes
associated with antioxidant defenses. Impaired NRF2 transactivation due
to insufficient PIN1 is a feature of autism.

\textbf{The FoxO Transcription Factors, Autophagy and mTOR}

The set of forkhead box (FoxO) transcription factors play an essential
role in neurodevelopment. FoxO3 enters the nucleus and activates the
gene expression of a set of proteins involved in diverse cellular
processes, including proliferation and autophagy {[}221,222{]}.
Conditional deletion of FoxO1, FoxO3 and FoxO4 strongly impairs
autophagy in developing neurons in the hippocampus {[}223{]}.
Furthermore, FoxO deficiency leads to altered dendritic morphology and
increased spine density in mouse hippocampal neurons {[}223{]}.

The PI3K/Akt/mTOR pathway involves complex feedback loops that regulate
the balance between anabolic and catabolic activities via two critical
branches, mTORC1 and mTORC2. mTOR signaling is disrupted in association
with autism {[}224{]}. Both the FoxO transcription factors and mTORC1
are downstream effectors of Akt. FoxO expression suppresses mTORC1 and
increases activation of the PI3K/Akt/mTORC2 pathway {[}225{]}.
Insufficient FoxO expression leads to impaired autophagy, while at the
same time promoting proliferation and differentiation through increased
activation of mTORC1. Impaired autophagy is a common feature found in
association with autism {[}226{]}. Autophagy is essential for synaptic
pruning, which is impaired in autism {[}115{]}.

PIN1 plays an essential role in facilitating the translocation of FoxO3
to the nucleus to effect activation of its target proteins {[}227{]}.
Thus, PIN1 deficiency leads to impaired autophagy due to inactivation of
FoxO3. The mTORC1 pathway activates the transcription factor NRF2, while
at the same time inhibiting autophagy {[}228{]}.

The degradation and clearance of damaged molecules in a cell are
achieved mainly through macroautophagy and the ubiquitin proteasome
{[}229{]}. mTORC1 is a well-established inhibitor of macroautophagy. It
not only inhibits the induction of autophagy by phosphorylating the core
proteins involved in initiation, but also targets each subsequent step
of the autophagy process {[}230{]}.

The rates of hearing loss, both moderate and severe, among autistic
children are much higher than the rates in the general population
{[}231{]}. Overactive mTORC1 in the cochlea is one of the critical
causes of age-related hearing loss {[}232{]}. Studies on mice revealed
that Rapamycin, a potent inhibitor of mTORC1 {[}233{]}, along with
N-acetylcysteine supplementation, could rescue cochlear hair cells from
injury due to oxidative stress. PIN1 protects hair cells from senescence
by inhibiting the PI3K/Akt/mTOR pathway {[}234{]}. Juglone is a drug
that is known to reduce expression of PIN1. Treatment of mice with
hydrogen peroxide and juglone induced ROS-related phosphorylation of
p53. This resulted in damage to the cochlea and hearing loss due to
cellular senescence {[}234{]}.

Altered dopamine signaling has been implicated as a contributing factor
in autism, and this could be due to impaired autophagy {[}235{]}.
Chronic lack of autophagy enhances evoked dopamine release from
dopaminergic neurons {[}236{]}.

\textbf{PIN1 and Epilepsy}

There is a high rate of co-occurrence between autism and epilepsy, and
many genetic defects are linked to both conditions {[}238,239{]}.
Glyphosate has been shown to cause seizures in round worms, and this
likely occurred through its action as a GABA-A receptor antagonist
{[}240{]}.

Recent studies reveal the role of PIN1 in the pathological development
of a range of neurodegenerative diseases, which also includes a
significant influence in the pathology of epilepsy. During epileptic
seizures, an abnormal electrophysiology persists in the brain {[}241{]}.
On the molecular level, the deregulation of synaptic transmissions is
considered as a major contributing factor for epileptic seizures
{[}242{]}. The balance of PIN1 isomerase activity would therefore be of
importance for epilepsy, since it regulates the excitatory glutamate,
N-methyl-D-aspartic acid (NMDA) and
alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the
inhibitory gamma-aminobutyric acid (GABA) and glycine receptors. All
these receptors are deregulated during epilepsy, as described in the Y
Chen et al. study {[}243{]}.

The acquisition of epileptic seizures in association with PIN1
deficiency has been observed in both animals and humans with impaired
PIN1 function, suggesting that the expression of PIN1 can inhibit the
symptoms of epilepsy {[}244{]}. PIN1 null mice have significantly
increased susceptibility to seizures and develop age-dependent
spontaneous epilepsy {[}245{]}. Recent studies in animals show that PIN1
deficiency increases the susceptibility to epileptic seizures upon
chemical stimuli. Moreover, in humans with epilepsy, PIN1 is
significantly downregulated whereas AMPA receptors are overactive. PIN1
deficient mice have a significantly increased risk to seizures, and
humans with epilepsy have increased phosphorylation of CaMKII and
increased levels of AMPA receptors in the neocortex. PIN1 knockout
increases the number of AMPA receptors through hyperphosphorylation of
CaMKII {[}245{]}. In animal experiments, CaMKII hyperphosphorylation is
reversed by the restoration of PIN1 expression in the prefrontal cortex
of their brains {[}245{]}. Social impairments in animal models of autism
can be ameliorated by antagonists of the AMPA receptors {[}246{]}. These
studies suggest that PIN1 upregulation can restore proper neural network
function and cortical synaptic organization in epilepsy.

\textbf{Autism, Asthma and the Regulation of PIN1}

As already described in earlier sections, activated DAPK1, in synergy
with p53, promotes the transcriptional activation of BAX, a condition
that results in neuronal cell apoptosis and death {[}191{]}. Neural
apoptotic cell death mediated by BAX also implies that PIN1 will be
deactivated by DAPK1 in neurons {[}86{]}. Similarly, in eosinophils,
apoptosis is prevented by activated PIN1 in the nucleus, and, by
contrast, apoptosis is magnified by the inhibition of PIN1 {[}247{]}.
Eosinophils are short-lived cells and, in common with neurons, are
highly differentiated and unable to divide. The activation of BAX in
eosinophils is also crucial for their mitochondrial mediated apoptotic
signaling, in order to prevent the emergence of long-lived eosinophils
that induce inflammation and asthma {[}248{]}. The
DAPK1-activation-PIN1-inhibition mediated expression of BAX, which is
important for the control of overwhelming eosinophil migration and
continued activation of long-lived eosinophils, constitutes a primary
pathologic factor in asthma {[}249{]}.

Although an earlier meta-analysis study had failed to prove a direct
relationship between asthma and autism {[}250{]}, there are serious
immune defects and comorbidities in autistic individuals that imply a
predisposition to asthma in autistic individuals {[}251{]}. Moreover, a
recent research investigation indicates that genetic relationships exist
between autism and asthma {[}252{]}.

The study of L Guglielmi et al. {[}253{]} provides a fine description of
autism spectrum disorder (ASD) associated pathogenesis linked to
potassium (K\textsuperscript{+}) channelopathies. Briefly, in ASD there
is a dysfunction of several K(+) channel types, often with a genetic
link, and these contribute to the repetitive behavior and social and
communication impairments encountered in autism. In the dendrites of
pyramidal neurons, there are numerous transient A-type potassium ion
channels that regulate action potential depolarizations and abnormal
excitatory events {[}254{]}. Kv4.2 is one of these crucial potassium
channel hippocampal proteins that controls neuronal plasticity and holds
a central role in learning and memory acquisition {[}255{]}. Quite
importantly, the functioning of Kv4.2 depends on the activity of PIN1.
When PIN1 becomes activated, it binds dynamically to the Thr-607
phosphorylated form of Kv4.2, leading to the isomerization of the
proline involved at the related pSer/Thr-Pro motif. This causes the
dissociation of Kv4.2 from its dipeptidyl peptidase 6 (DPP6) subunit,
inhibiting the Kv4.2 function for protection from excess neuron
excitability through depolarization {[}256{]}. The isomerization induced
by PIN1 in Kv4.2 is important for proper neuronal and cognitive function
{[}256{]}.

Furthermore, in contrast to PIN1-mediated neuron over-excitability due
to the loss of Kv4.2 function, other studies that relate to Alzheimer's
disease (AD) indicate that mutations in the synaptic scaffolding
protein, SHANK3, which associates with autism {[}257{]}, render the loss
of PIN1 activity important for the regulation of synaptic plasticity in
AD {[}171{]}. Given the aforementioned evidence, justifiable scientific
grounds suggest a common PIN1-mediated pathogenic mechanism associated
with both asthma and neurological defects encountered in ASD. PIN1 is
significantly implicated in other studies of the pathogenesis of asthma
by inducing eosinophilic inflammation through the upregulation of TGF-\selectlanguage{greek}β\selectlanguage{english}1
{[}258{]}. In this concept, the mode of induction or inhibition of
apoptosis by the DAPK1--PIN1 interactive regulation becomes important
for the onset of both asthma and neurologic defects in autism
{[}86,191{]}.

\textbf{The SARS-CoV-2 mRNA Vaccines: Will They Increase Autism Rates?}

The US Centers for Disease Control are now recommending that the
SARS-CoV-2 mRNA vaccine be administered to children as young as six
months of age, and also to pregnant women {[}259{]}. We believe there is
reason to be concerned that this policy may lead to increases in the
prevalence of autism both in vaccinated infants and in the offspring of
vaccinated pregnant women. It has become very clear that the SARS-CoV-2
spike protein is extremely toxic, and it may be the primary cause of
observed severe vaccine side effects following mRNA vaccination. The
spike protein itself is likely a major cause of myocarditis following
vaccination, as circulating spike protein, both free and antibody-bound,
was found in subjects who developed myocarditis after the vaccine, but
not in the control subjects {[}260{]}. A study on 28 cases of fatal
myocarditis immediately following mRNA vaccination for SARS-CoV-2
established that all 28 deaths were most likely linked to the vaccine
{[}261{]}. The spike protein is predicted to cause neuroinflammation and
neurodegenerative disease, in part through its prion-like properties
{[}262,263{]}.

The lipid nanoparticles in the vaccine are designed so as to protect the
mRNA from degradation, and, furthermore, the mRNA itself has been
engineered to resist enzymatic breakdown through the substitution of
methylpseudouridine for all of the uridine residues {[}264{]}. The
synthetic cationic lipids assure that the mRNA will be released from the
endosome, escaping lysosomal degradation, and then be persistently
translated into spike protein. While mRNA normally degrades within a few
hours, vaccine spike antigen and mRNA can persist for up to eight weeks
in lymph node germinal centers {[}265{]}.

The nanoparticles can breach the blood brain barrier, and the mRNA
nanoparticles can be phagocytized by microglia in the brain and then
translated into spike protein, stimulating a massive immune response.
This causes upregulation of TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-1\selectlanguage{greek}β, \selectlanguage{english}and IL-6, stimulating ROS
production and neuroinflammation. Neuroinflammation in turn provokes
astrocytes to release excessive glutamate into the synapse,
overstimulating the NMDARs and causing neuroexcitotoxicity {[}266{]}.
This leads to a reduction in BDNF signaling and impaired
neuroplasticity, as is seen in schizophrenia and autism {[}267{]}. As we
have seen, extracellular glutamate interferes with cystine uptake in
neurons, leading to glutathione deficiency. A recent review paper has
proposed that glutathione deficiency may be at the core of COVID-19
pathophysiology {[}268{]}. Glyphosate's ability to deplete glutathione
would therefore likely lead to more severe outcomes from COVID-19 and/or
more severe adverse reactions to the mRNA vaccines.

A seminal study by Erdogan et al. on rat pups found strong evidence that
the mRNA vaccines cause autism-like symptoms in rats. Pregnant rat dams
were exposed to a full adult dose of the BNT162b2 vaccine, and the
offspring were carefully evaluated for behavioral issues and motor
performance, as well as monitoring for any changes in brain chemistry.
Exposed male rat pups, but not female pups, exhibited pronounced
autism-like behaviors, including repetitive behaviors, impaired social
interaction, as well as impaired coordination and agility. Notably, the
exposed male offspring were found to have statistically significant
decreased expression of BDNF and WNT (p \textless{} 0.01) and
significantly increased expression of mTOR (p \textless{} 0.01)
{[}269{]}.

BDNF is an important player in WNT signaling, and its expression has
been shown to be essential for synapse maturation in the hippocampus
mediated by neuroligin {[}270{]}. Downregulation of BDNF leads to
decreased levels of Bcl2 through impaired Akt signaling, with a
resulting increase in apoptosis in neurons, a mechanism that has been
proposed as potentially being responsible for the pathogenesis of autism
{[}271{]}. We have already seen that WNT signaling is decreased
following exposure to glyphosate, making these injections
synergistically toxic with glyphosate {[}118{]}. Overexpression of mTOR
has been linked to increased spine density in excitatory synapses in
autism {[}272{]}. As we have already stated, an overactive mTOR pathway
impairs microglial autophagy, resulting in decreased clearance of
unproductive synapses {[}116{]}.

In the Erdogan et al. study, post-mortem analyses showed that exposed
male pups also had significantly fewer neurons in specialized regions of
the hippocampus compared to male pups of the unvaccinated mothers, as
well as lower counts of Purkinje cells in the cerebellum {[}269{]}.

While the rat dams in this experiment was exposed to a much higher dose
of the vaccine than would be appropriate given their weight, it is also
the case that the rat ACE2 receptor has a much reduced capacity to
facilitate uptake of the spike protein compared to the human ACE2
receptor, making rats far less susceptible to SARS-CoV-2 {[}273{]}.

We have shown that children with autism have impairments in melatonin
synthesis, and that glyphosate exposure reduces melatonin levels in rats
{[}39{]}. It has been proposed that melatonin supplementation can be
therapeutic in treating long COVID, through its anti-inflammatory,
antioxidant and immune enhancing properties {[}274{]}. A study on mice
humanized to express the human ACE2 protein and exposed to SARS-CoV-2
found that melatonin therapy inhibited SARS-CoV-2 brain entry and
protected brain endothelial cells from damage. They showed that
melatonin inhibits virus-induced damage of cerebral small vessels,
diminishes brain inflammation, and decreases viral load in the brain.
This result suggests that melatonin deficiency, such as is seen in
autism and induced by glyphosate, would lead to increased risk to severe
COVID as well as vaccine adverse reactions.

At the beginning of this paper, we noted the standard categorization of
autism onset as ``early,'' typically onset prior to age 2; and
``regressive,'' with onset after age 2. We cited studies that have shown
that over 50\% of regressive cases of autism displayed
subtle-yet-perceivable sensory and/or behavioral abnormalities prior to
regression, i.e. during the ``normal'' developmental months. We propose
here that the risk of developing the sensory and behavioral changes
characteristic of autism -- along with the concurrent pathophysiology
described in this paper - lies on a continuum. Differing levels
of\emph{in utero} , neonatal, and postnatal glyphosate exposure, against
a background of other risk factors, helps explain this chronological
gradient of autism symptom onset.

We strongly suggest that glyphosate may be playing a significant (and
possibly central) role in contributing to the autistic phenotype.
Current CDC recommendation regarding COVID-19 vaccination is that
infants should be vaccinated beginning at 6 months of age {[}275{]}
Furthermore, prenatal and postnatal exposure to the constituents of
COVID-19 mRNA vaccines via maternal, neonatal and early-postnatal
periods is potentially an additional strong push toward that same
phenotype for the reasons we have explained above. For children
manifesting as regressive autism, we are concerned that mRNA vaccination
may contribute the spark of neuroinflammation that is the tipping point
for an infant with excessive prior exposure to glyphosate and/or other
environmental factors, particularly when combined with risk genes. In
this regard, we agree with the letter published by Mawson (2019)
regarding the finding of increased autism following MMR vaccination:
``Many factors, including receiving the MMR vaccine and other vaccines,
may be combining with as-yet unidentified host and environmental factors
to cause {[}autism{]}.'' {[}276{]}. We believe this paper makes a
compelling case that one of those environmental factors has now been
identified.

\textbf{Conclusion}

The incidence of autism has increased dramatically over the past two
decades. While its causal factors are most certainly multifactorial
(toxicants, genetics, nutrient deficiencies, etc.), there are numerous
cellular and biochemical pathologies that are shared by virtually all
individuals with the condition. This paper has focused on what we
believe to be a prime suspect as a causal environmental factor,
glyphosate exposure. We have itemized several biochemical and
histological pathologies associated with autism throughout this paper.
We weave into this narrative a review of the literature to show
substantial evidence that exposure to glyphosate has also been
associated with the same pathologies found in individuals with autism.
We also highlight a unique role for melatonin in protecting against
development of those same neurological pathologies, and review evidence
that glyphosate exposure also suppresses melatonin production.

Another prominent focus of this paper is on what we believe to be the
most important pathways through which glyphosate, melatonin suppression,
glutamate neuroexcitotoxicity and potentially other causal factors lead
to the phenotype of autism, namely suppression of cellular isomerase
PIN1 activity. Its suppression, whether by glyphosate exposure,
melatonin deficiency, DAPK1 activation, glutathione deficiency,
oxidative stress, or other causes, is the first domino to fall,
initiating a long series of downstream events that result in all the
underlying pathological changes we have catalogued as associated with
autism. Because of both the direct and indirect role PIN1 plays in so
many cellular regulatory pathways and processes, its loss of activity
has catastrophic consequences leading to autism pathology. This becomes
perhaps most explicitly manifest in the developing neurological system
of infants and children, making them most vulnerable to the pathological
changes PIN1 suppression induces. Figure 3 provides a graphical
representation of the processes we have identified in this paper leading
to autism in children.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=1.00\columnwidth]{figures/image3/image3}

\end{center}
\end{figure}

\textbf{Figure 3: The complex processes by which glyphosate damages the
infant brain, leading to impaired neurodevelopment and autism spectrum
disorder.} PIN1 plays a central role in the pathology. Glyphosate
plausibly induces severe depletion in glutathione levels in the brain
via its induction of oxidative stress and its disruption of melatonin
synthesis in the brain. Increased ROS and elevated expression of DAPK1
both contribute to the loss of PIN1 activity. These three features - low
glutathione, oxidative stress, and reduced PIN1 activity -- disrupt
brain development, resulting in the characteristic morphological and
behavioral features of autism.

We end our review with a note of caution about mRNA vaccinations in
general, but especially for children, and for autistic children most
directly. We have called attention to the established pathways whereby
the mRNA and associated LNPs can migrate to the brain and induce
neuroinflammation, creating many of those same pathological imbalances
we previously showed to be associated with autism.

Given the ominous rise in the incidence of autism now happening around
the globe, we believe it is imperative that distribution and use of
glyphosate, and administration of COVID-19 mRNA-LNP vaccinations to
pregnant women and infants be halted immediately, while the mechanisms
behind their potential connection to autism -- and possibly a wide range
of other diseases -- can be definitively ruled out through additional
detailed research.

\textbf{References}

\begin{enumerate}
\tightlist
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