11. The Regulation of Human Prion Protein and β-Amyloid Genes
The PRNP gene located in chromosome 20 in humans codes for
PrPC in the central nervous system and several other
tissues [41]. This is a highly conserved housekeeping gene, and it
is subject to many transcription factors functioning in its promoter and
thus regulating its expression. Amongst many others putative sequences
for transcriptional activation by activator protein 1 (AP-1), SP1 and
SP2 (members of the SP/KLF family of transcription factors) have been
identified as PRNP promoters.
Importantly, a short GC rich region is located upstream from thePRNP gene promoter. These GC-rich regions have the potential to
form G-quadruplex (G4) structures and therefore regulate gene
disease-related expression, as they are subject to favorable binding by
p53. Binding of p53 to GC regions forming G4s has been shown to initiate
a series of cellular effects related to disease [95,96].
Furthermore, it has been shown that the PRNP promoter region
harbors a sequence matching the binding sequence of p53. p53 binds
directly to the suspected sequence, behaving as a potent
PrPC transcriptional activator and enhancer of its
mRNA expression [97]. In summary, p53 causes an increased expression
of PrPC.
RNA translational regulation is considered an important contributor to
PrPC conversion to infectious PrPSC.
Beyond DNA, it has been shown that the messenger RNA of
PrPC contains five naturally existing consecutive
regions forming G4s that are susceptible to G4 binding ligands [98].
In this respect, p53 can be regarded as an RNA chaperone that is able to
facilitate the folding of G4s and hence stabilize their structure
[99]. G4s in 5’-untranslated mRNA regions are found in multiple
neurodegenerative diseases and have been shown to inhibit translation
and initiate cap-independent translation [100].
The amyloid precursor protein (APP ) gene coding for the APP in
humans is located on chromosome 21. Viewing its promoter sequence, it
can be designated as a housekeeping gene like the PRNP gene.APP shares some important promoter sequences with PRNPlike AP-1 and Sp1, amongst many others, which however differ from the
sequences in the PRNP promoter. This suggests that both genes can
be partly transactivated by the activity of common transcription factors
[101].
APP mRNA is expressed in a variety of tissues, including muscle, the
immune system, and many organs such as the thymus, pancreas, kidneys,
the lung and others, in addition to its active expression in the nervous
system. However, different variants of APP are cell-type specific in
their expression [102].
The variants of APP include APP-like protein-1 (APPL1 gene
located on chromosome 21) and APPL2 (APPL2 gene located on
chromosome 11), which are both type 1 transmembrane proteins with
similar structure and topology. Only APP itself, however, contains the
Aβ sequence. The fibrillary form of Aβ (40-42 amino acids), found and
constituting the primary source of plaques in brains of patients
suffering from AD and Down syndrome, originate only from APP
proteolysis. The full length of human APP sustains proteolysis mainly
via the α,β,γ-secretases. The derived amino acid sequence of Aβ results
from the β-site APP cleaving enzyme 1 (BACE-1) or else β-secretase
cleavage yielding APPsβ and APPCTFβ (βAPP) fragments of APP. Thereafter,
the cleavage of γ-secretase on βAPP finally yields Aβ and the APP
intracellular domain (AIDC) fragments (for details see [103]).
Moreover, the AIDC fragment is also produced by α-secretase and
subsequent γ-secretase activity.
γ-Secretase is also called presenilin-dependent γ-secretase, since it
encompasses presenilin (PS) transmembrane proteins in its catalytic
subunit (PS1 or PS2) [104]. In this respect, it has been established
that γ-secretase/presenilin-dependent generation of AIDC operates as a
transcriptional activator of p53, increasing p53 activity and triggering
p53-associated cell death. Moreover, mutations in transcription factor
Sp1 increase the p53 activity in vitro and in brains of patients
affected with familial Alzheimer’s disease (FAD) [97]. Mutations on
Sp1 are considered as a causative factor for FAD.
The tumor suppressor p53, once generated through the
γ-secretase/presenilin dependent transcriptional activation of theTP53 gene by AIDC bound to Fe65 and Tip60 cofactors, then acts on
the promoter of PrPC and induces the expression of
PrPC mRNA. The p53, γ-secretase/presenilin dependent
transactivation of PrPC expression is abolished in a
p53-deficient environment. Thus, it is ultimately the PSs (PS1 or PS2)
which exert rate-limiting control over PrPC expression
through their ability to generate AIDC. Finally, βAPP overexpression
increases PrPC expression, whereas βAPP depletion
results in lower PrPC expression, in both in
vitro and in vivo experiments, indicating also the controlling
role of BACE-1 activity over PrPC expression [96].
Thus, the metabolism of APP that produces amyloidogenic products also
induces increased production of PrPC.