7. The Relations of PrPC and APP to
Phosphorylation Pathways and Beyond
Although PrPC participates in vitally important
cellular functions (Table 1), the conformational conversion of
PrPC to PrPSC is the hallmark to
prion disease progression, and the prerequisite for this conversion is
the expression and presence of PrPC. In the absence of
endogenous PrPC there is an overwhelming resistance to
the development of prion disease [67].
On the one hand, the role of normal isoform PrPCpresence seems to be protective for cells, as for example is the case
where the suppression of PrP mRNA expression leads to onset of premature
aging processes [66]. On the other hand, the tissues that do not
express PrPC are resistant to PrPSCtoxicity. It is the infectious PrPSC which aggregates
to form fibrils, and the oligomers of these fibrils that are highly
infectious and neurotoxic, and it is their relations to phosphorylation
pathways that constitute the pathogenesis mechanisms of prion and
prion-like diseases [13,68,69]. Additionally, the intramolecular
regions (tandem repeats) of tau protein strongly interact with the
octapeptide repeats of wild type PrP, and more strongly with the mutant
types of PrPSC, to form strongly bound complexes
[70]. This highlights the potential mutual involvement of both
PrPC and tau proteins in the context of common
pathogenic mechanisms causing prion disease, as well as tau-related
neurodegeneration. The prion-like propagation that ensues also involves
β-amyloid protein aggregation, which induces tauopathy as it is
encountered in Alzheimer’s Disease (AD) [68,69,71].
Importantly, the acceleration of PrPSC formation
through the cellular pathways just described drives forward, in a
positive-feedback manner, the initiation and progression of tau-related
pathology, including the production and aggregation of tau proteins. It
is within this context that the events of inter-related
neurodegenerative pathogenesis mechanisms transpire. Moreover, the
advance and proliferation of misfolded PrP to an at-risk human
organism’s neuronal tissues precedes the onset of neuro-pathogenesis
disease mechanisms, suggesting that PrPCover-expression is a major contributor to the onset of prion and
prion-like diseases [68].
Protein aggregation is common in some neurodegenerative diseases, such
as AD, Parkinson’s Disease (PD) and Huntington’s Disease (HD). However,
another common characteristic of prion and prion-like diseases is the
improper conformation alignment of their disease-related proteins, i.e.,
PrP for prion diseases, tau and β-amyloid for AD and HD respectively,
and α-synuclein for PD. The improper protein conformations are the
tertiary structure alterations from α-helix to β-pleated sheets that
then favorably follow the aggregation pathways which are thereafter
resistant to proteasome degradation pathways [40]. In this regard,
even slight modification in the amino acid terminus of proteins means an
alteration in the N-degron recognition signaling for degradation
[72].
The p38 MAPK phosphorylation pathway has been described as a
disease-associated sequela of exposure to the synthetic mRNAs coding for
the SARS-CoV-2 spike protein. Moreover, the p38 MAPK phosphorylation
pathway inhibits autophagy. This also leads to increased levels of p53.
In this way, the formation of the PrPSC infectious
isoform triggers a molecular cascade of neurotoxic events that involve
the p38 MAPK pathway [60,73].