controls found that six of the Parkinson’s patients had had an earlier diagnosis of Bell’s palsy, whereas none of the control patients had [18]. There’s also a link between autism and Parkinson’s disease. A study on autistic adults over 39 years old found that one third of them had symptoms that meet the criteria for a Parkinson’s diagnosis [19].
Prion Diseases
Prion diseases are a group of severe neurodegenerative diseases that are caused by misfolded prion proteins. The most common prion disease in humans is the always-fatal sporadic Creutzfeldt-Jakob disease (CJD), which accounts for more than 85% of the cases [20]. Prion diseases are more specifically called transmissible spongiform encephalopathies (TSEs), and infection can spread through exposure to misfolded proteins as “infective” agents, without requiring a live pathogen [20]. PrP is the name given to the specific prion protein associated with these TSEs. Misfolded PrP proteins act as a seed or catalyst that then recruits other molecules of PrP to misfold in the same way and glom together into pathogenic fibrils.
MADCOW, the disease that affected a large number of cows in Europe beginning in the 1990s, is probably the best-known TSE. While eating beef from an infected animal is a very rare risk factor, most cases of Creutzfeldt-Jakob disease occur for unknown reasons, and no other risk factors have been identified. A study based in Switzerland confirmed that many patients who died of Creutzfeldt-Jakob disease had detectable levels of a prion protein in their spleen and muscles, in addition to the olfactory lobe and the central nervous system [21]. More generally, diseases involving misfolded PrPs have consistently been found to involve an initial early phase of prion replication in the spleen which happens long before overt symptoms appear [22, 23]. This point becomes important when we consider whether the COVID-19 vaccines might cause prion diseases.
PrP has a unique feature that it contains multiple copies of a characteristic motif in its amino acid sequence that is called a “GxxxG” motif, also known as a “glycine zipper” [24]. These proteins normally fold into a characteristic shape called an alpha helix, which allows the protein to penetrate the plasma membrane. The glycines in the zipper motif play an essential role in cross-linking and stabilizing alpha helices [25]. This glycine zipper motif is also a common characteristic of many transmembrane proteins (proteins that cross the membrane of the cell). Indeed, the coronavirus spike protein has a GxxxG motif in its transmembrane domain (specifically, GFIAG -- glycine, phenylalanine, isoproline, alanine, glycine) [26]. There is a platform called “Uniprot” where you can look up the sequence of specific proteins. The Uniprot entry for the SARS-CoV-2 spike protein has five glycine zipper sequences altogether [27]. According to J. Bart Classen, the SARS-CoV-2 spike protein has the ability “to form amyloid and toxic aggregates that can act as seeds to aggregate many of the misfolded brain proteins and can ultimately lead to neurodegeneration.” [28]
Many neurodegenerative diseases have been linked to specific proteins that have prion-like properties, and these diseases are characterized as protein-misfolding diseases or proteopathies [29]. Like PrP, prion-like proteins become pathogenic when their alpha helices misfold as beta sheets, and the protein is then impaired in its ability to enter the membrane.
These diseases include Alzheimer’s, amyotrophic lateral sclerosis (ALS), Huntington’s disease and Parkinson’s disease, and each of these is associated with a particular protein that misfolds and accumulates in inclusion bodies in association with the disease. We already saw that Parkinson’s disease is characterized by Lewy bodies in the substantia nigra that accumulate misfolded α-synuclein. Glycines within the glycine zipper transmembrane motifs in the amyloid beta precursor protein (APP) play a central role in the misfolding of amyloid beta linked to Alzheimer’s disease (Decock et al., 2016). APP contains a total of four GxxxG motifs (one fewer than the spike protein).
A case study presented the case of a man who developed CKD simultaneously with symptomatic COVID-19. The authors proposed that infection with SARS-CoV-2 precipitates or accelerates neurodegenerative diseases [30]. A theoretical paper published by researchers in India showed that the spike protein binds to a number of aggregation-prone prion-like proteins, including amyloid beta, α-synuclein, tau, PrP and TDP-43. They argued that this could initiate aggregation of these proteins in the brain, leading to neurodegeneration [31].