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
PrPC and to induction of IL-6 and TNF-α cytokines
through p38/CREB, and p65/NF-κB activation. Accumulation of
PrPC is a predisposing factor for the conformational
alteration to PrPSC and therefore prion and prion-like
diseases. PrPSC, 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
PrPC and PrPSC 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].