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.