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Source: NeuroCOVID  Mar 01, 2022  1 year, 6 months, 3 weeks, 4 days, 15 hours, 5 minutes ago

University of Oklahoma Study Discovers How The Polypeptide SK9 From The Envelope Protein Of SARS-COV-2 Causes Parkinson’s Disease!

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University of Oklahoma Study Discovers How The Polypeptide SK9 From The Envelope Protein Of SARS-COV-2 Causes Parkinson’s Disease!
Source: NeuroCOVID  Mar 01, 2022  1 year, 6 months, 3 weeks, 4 days, 15 hours, 5 minutes ago
NeuroCOVID: Many individuals are simply ignorant and are not aware that already numerous studies have already showed that neurotoxic proteins from the SARS-CoV-2 virus is able to cause a variety of neurodegenerative damage to the human host brain that will ultimately lead to diseases like Alzheimer, Parkinson’s Disease and also Dementia.

Among many highly credible medical researchers and scientists this is already a confirmed consequence of SARS-CoV-2 infection irrespective of whether one was asymptomatic or even had only mild symptoms upon infection and these conditions will rapidly develop if not immediately for a few, will materialize slowly over months and not more than 3 to 5 years from infection!,-promoting-accelerated-amyloid-formation-and-parkinson-s-disease
In this new study by researchers from the University of Oklahoma, the detailed mechanism of how SARS-CoV-2 envelope proteins causes Parkinson’s Disease in those infected.
Utilizing molecular dynamic simulations, the research team studied whether amyloidogenic regions in viral proteins can initiate and modulate formation of α-synuclein aggregates, thought to be the disease-causing agent in Parkinson’s Disease.
The NeuroCOVID study team choose as an example, the nine-residue fragment SFYVYSRVK (SK9), located on the C-terminal of the Envelope protein of SARS-COV-2.
The study team probed how the presence of SK9 affects the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs.
The study findings showed that the viral protein fragment SK9 alters α-synuclein amyloid formation by shifting the ensemble toward aggregation-prone and preferentially rod-like fibril seeding conformations. However, SK9 has only little effect of the stability of pre-existing or newly-formed fibrils.
The study findings were published on a preprint server and are currently being peer reviewed.
The study findings demonstrated the impact of an amyloidogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) protein fragment named SFYVYSRVK (SK9) on the α-synuclein monomers and fibrils, a potential risk factor for Parkinson's disease.
To date, while most COVID-19-infected individuals completely recover from the disease, there isn't much data regarding the long-lasting or delayed neurological consequences of SARS-CoV-2 infection.
Symptoms such as loss of smell and other neurological deficits have been reported during acute SARS-CoV-2 infection. Additionally, several reports have implied the potential risk of Parkinson's disease and other neurodegenerative disorders linked with SARS-CoV-2. (see above links from Thailand Medical News.)
A probable mechanism of Parkinson's disease following COVID-19 is the SARS-CoV-2-mediated amyloid generation as aggregates of alpha-synuclein (α-Syn).
A few in vitro reports suggest that SARS-CoV-2 accentuated α-Syn amyloid formation by interaction with amyloidogenic regions on the nucleocapsid (N), envelope (E), and spike (S) proteins.
Interestingly, a mechanism similar to Alzheimer's disease has been hypothesized for the enhanced amyloid formation leading to Parkinson's disease in COVID-19, which involved the formation of amyloid fibrils as an immune response to infection leading to entrapment and neutralization of the pathogen.
Unfortunately, in-depth information about the exposure to SARS-CoV-2, the appearance of fibrils, and resulting disease symptoms are not available.
The study team examined how the interaction of the SARS-CoV-2 residual fragment named SK9 located on the C terminal of the E protein impacts the conformational ensemble of α-synuclein monomers and the stability of two resolved fibril polymorphs called the rod and the twister structures.
A detailed helix-rich model of the α-synuclein monomer structure was resolved employing nuclear magnetic resonance (NMR) solution in the micellar environment and was stored in the Protein Data Bank (PDB) under the identification code:1XQ8. The team evaluated the binding of the SK9 with α-synuclein and whether it alters the α-synuclein's conformational ensemble by employing a complementary set of molecular dynamic simulations. For assessing the stability of the α-synuclein fibrils rod and twister polymorphs, decamers made of five layers and two protofilaments were generated using cryogenic electron microscopy (cryo-EM) structures.
The study findings indicate that although the rod and twister polymorphs share a bent β-arch architecture, they exhibit distinct inter-protofilament interfaces. While the interface in twister polymorph was formed by the hydrophobic aggregation-triggering non-amyloid-β component (NAC) region from residues G68-A78, the preNAC region from residues E46-A56 comprises the interface in rod polymorph.
Surprisingly, the rod polymorph's C-terminal residues were more organized than the twister polymorph, implying higher stability of the rod polymorph than the twister. Nonetheless, six frequent mutations of α-synuclein: A53V, A53T, A53E, G51D, H50Q, and E46K, destabilized the rod structure's preNAC interface but did not disrupt the twister polymorph, probably shifting the population from rod to twister.
Detailed visual inspections show that in the presence of the SK9, the α-synuclein monomers were more strand-like and extended. Further, the ensemble of the α-synuclein in the presence of SK9 shifted toward more solvent-exposed, looser-packed, and larger conformations. This inference implies that the binding of SK9 exposes more hydrophobic residues in α-synuclein and probably alters the α-synuclein amyloid monomer production by changing the ensemble towards more aggregation-prone conformations.
It was found that the interaction of SK9 further augments the selectivity of α-synuclein ensembling in the rod-like fibril seeding conformations by inducing higher flexibility, exposure of residues, and a lowered helix-propensity, particularly in the segment E46-A56 that form in the rod fibril polymorph during the inter-protofilament interface. In addition, the interaction between SK9 and the rod fibril substantially enhanced the frequency and lifetime of two contacts, E46-K80 and V52-A76.
However, SK9 has little impact on the stability of newly formed or pre-existing rod and twister fibrils. Although there was a stabilization of twister fibril geometry upon the binding of SK9, it does not lead to significant changes in twister fibril quantities.
The research data indicate that since the mutations present in α-synuclein, which impacted the stability of rod fibrils, were associated with Parkinson's disease, the shift in frequency within rod and twister fibrils will change the likelihood of developing Parkinson's disease. This inference is especially significant during COVID-19 because SARS-CoV-2 SK9 augments the probability of forming rod polymorph.
The research findings indicate that the presence of SK9 alters the ensemble of α-synuclein to more aggregation-prone conformations.
Interestingly, although the twister fibril was considered more cytotoxic, the interaction of SK9 led to the preference for α-synuclein monomer conformations that probably seed the rod-like fibrils, which were associated with a risk for Parkinson's disease.
Importantly, additional simulations employing other amyloidogenic segments of SARS-CoV-2 proteins, specifically in the Spike, are required to understand whether this effect is selective for SK9. Further, the study indicates the binding of SK9 with the rod and the twister fibril polymorphs had only a minor impact on the stability of these fibrils.

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