Mitogen Activated Protein Kinase (MAPK) Activation, p53, and Autophagy Inhibition Characterize the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike Protein Induced Neurotoxicity

Cureus. 2022 Dec 9;14(12):e32361. doi: 10.7759/cureus.32361. eCollection 2022 Dec.


The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein and prions use common pathogenic pathways to induce toxicity in neurons. Infectious prions rapidly activate the p38 mitogen activated protein kinase (MAPK) pathway, and SARS-CoV-2 spike proteins rapidly activate both 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, molecular mimicry, elevated intracellular p53 levels and reduced Wild-type p53-induced phosphatase 1 (Wip1) and dual-specificity phosphatase (DUSP) expression in neurons in the disease process. The pathways induced by the spike protein via toll-like receptor activation induce both the upregulation of PrPC (the normal isoform of the prion protein, PrP) and the expression of β amyloid. Through the spike-protein-dependent elevation of p53 levels via β amyloid metabolism, increased PrPC 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. An autoimmune reaction via molecular mimicry likely also contributes to neurological symptoms. Overall results suggest that neurodegeneration is in part due to the intensity and duration of spike protein exposure, patient advanced 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.

Keywords: aging; autoimmunity; autophagy; covid-19; mrna vaccines; p53; prion and prion-like diseases; sars-cov-2 spike protein; senescence; wip1.

Publication types

  • Review