14. The Relation of SARS-CoV-2 Spike-Protein-Induced Neurotoxicity to Age and the Inhibition of Autophagy
The relationship between age and the reduced cellular capability for autophagy, in combination with p53 accumulation during autophagy inhibition, constitutes the proposed model of spike-protein-induced neurotoxicity presented in Figure 1. In this model, pathogenesis is augmented by a) aging, which leads to impaired autophagy, and b) p53 accumulation, due to the inhibition of the UPS system for degradation [106,107].
Under autophagy inhibition and p38 MAPK activation, a detrimental cascade of events ensues: Wip1 deactivation, and, hence, inhibition of p53 dephosphorylation, concurrent with BACE-1 activation, both promote AIDC positive regulation of the TP53 gene and the p53-dependent transcriptional activation of the PRNP gene. These events set the stage for the cascade of cellular events leading to prion protein aggregation and subsequent pathologies.