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].