MAPK Activation, P53 and Autophagy Inhibition Characterize the SARS-CoV-2 Spike Protein Induced Neurotoxicity

Abstract

The SARS-CoV-2 spike protein and prions use common pathogenic pathways to induce toxicity in neurons. Infectious prions activate the p38 mitogen activated protein kinase (MAPK) pathway, and SARS-CoV-2 spike proteins induce the p38 MAPK and c-Jun NH2-terminal kinase (JNK) pathways through toll-like receptor signaling, indicating the potential for similar neurotoxicity, causing prion and prion-like disease. In this review we analyze the roles of autophagy inhibition, elevated intracellular p53 levels and reduced Wild-type p53-induced phosphatase 1 (Wip1) and dual-specificity phosphatase (DUSP) expression in neurons. The pathways induced by the spike protein via toll like receptor activation induce both PrP upregulation and β amyloid expression. Through the spike-protein-dependent elevation of p53 levels via β amyloid metabolism, increased PrP expression can lead to PrP misfolding and impaired autophagy, generating prion disease. We conclude that, according to the age of the spike protein-exposed patient and the state of their cellular autophagy activity, excess sustained activity of p53 in neurons may be a catalytic factor in neurodegeneration. We conclude that neurodegeneration is in part due to intensity and duration of spike protein exposure, patient age, cellular autophagy activity, and activation, function and regulation of p53. Finally, the neurologically damaging effects can be cumulatively spike-protein dependent, whether exposure is by natural infection or, more substantially, by repeated mRNA vaccination.

SARS-CoV-2 amyloid, is COVID-19-exacerbated dementia an amyloid disorder in the making?

“…Complexes involving more than one amyloid-forming compound may play a role in vivo leading to toxic fibril forms (Young et al, 2015) and this raises the possibility that copolymers involving SARS-CoV-2 spike protein amyloid and Aß (Idrees and Kumar, 2021) could play a role in triggering AD-like pathology. The SARS-CoV-2 spike protein is itself neurotoxic and activates Aß expression (Kyriakopoulos et al, 2022) providing a clear link between these two amyloid-forming proteins and neurotoxicity.…”