Figure 1. The phosphorylation pathway induced by SARS-CoV-2 spike protein leads to prion     disease. The spike protein activates TLR4 signalling to induce p38 MAPK and NF-κB. Moreover, the     spike protein also stimulates IRAK4 signalling to induce p38 MAPK, NF-κB and cytokine storm and     inhibits DUSPs and Wip1, causing sustained p53 expression. Wip1 deficiency caused by     JNK-       microRNA-16 activation leads to diminished p53 deactivation and thus, transcriptional activation     of the human prion protein promoter. This leads to increased accumulation of PrP^C and to     induction of IL-6 and TNF-α cytokines through p38/CREB, and p65/NF-κB activation.     Accumulation of PrP^C is a predisposing factor for the conformational alteration to PrP^SC and     therefore prion and prion-like diseases. PrP^SC, once formed, will further enhance p38 MAPK     activation. Adapted from: [1,10,13,30,84-86,,94,97,112,82,121].

The release of p53 from dephosphorylation by DUSP1 or Wip1 drives the neuron towards the onset of prion and protein folding diseases and establishes the cellular circumstances whereby the SARS-CoV-2 spike protein can play a central role in creating neurotoxicity and predisposing exposed individuals toward neurodegeneration. However, this process is age-dependent, and it is related to the cellular ability to induce autophagy. Although the clear relationship between PrP^C and PrP^SC formation has not yet been established, the generation of infectious prions is clearly related to the induction of the p38 MAPK pathway, which is also induced by the spike protein in conjunction with JNK in several ways. Figure 2 illustrates the potential mechanisms of the SARS-CoV-2 spike protein, derived either from natural infection or from synthetic mRNAs coding for SP, that induce prion and prion-like disease. The spike-protein-induced neurotoxicity mechanism depends on a) the age of the spike protein recipient and b) the impairment of suppression of prion disease through macro-autophagy [1,13,91,110,82].