SARS-CoV-2 "nucleocapsid" and protein misfolding

Are misfolded proteins just bad ?

I am rather “glad” other events and more pertinent information came up, so a substack that would merely touch on one subject matter will now touch on many, and introduce one of my outlandish ideas (I don’t dare call it a hypothesis, even though there will be decent scientific merit to it). First things first, a paper I have mentioned a few times.

SARS-CoV-2 N-protein induces the formation of composite α-synuclein/N-protein fibrils that transform into a strain of α-synuclein fibrils

The presence of deposits of alpha-synuclein fibrils in cells of the brain are a hallmark of several αsynucleinopathies, including Parkinson's disease. As most disease cases are not familial, it is likely that external factors play a role in disease onset. One of the external factors that may influence disease onset are viral infections. It has recently been shown that in the presence of SARS-Cov-2 N protein, αS fibril formation is faster and proceeds in an unusual two-step aggregation process. Here, we show that faster fibril formation is not due to a SARS-CoV-2 N-protein-catalysed formation of an aggregation-prone nucleus. Instead, aggregation starts with the formation of a population of mixed αS/N-protein fibrils with low affinity for αS. After the depletion of N-protein, fibril formation comes to a halt, until a slow transformation to fibrils with characteristics of pure αS fibril strains occurs. This transformation into a strain of αS fibrils subsequently results in a second phase of fibril growth until a new equilibrium is reached. Our findings point at the possible relevance of fibril strain transformation in the cell-to-cell spread of the αS pathology and disease onset.

There has been ample debate among researchers and scientists on the dynamics of “bad” protein accumulation in regard to SARS-CoV-2, from small sections of its other proteins, and how they may create the right cellular conditions for the accumulation of said proteins.

The most pertinent aspect of this paper is that the N protein doesn’t create or incentivize the accumulation of misfolded Alpha-Synuclein (aS), but the N protein starts mixing with aS and creates a mixture of both proteins with a low affinity towards aS. So far a lot of papers focused on the fact that SARS-CoV-2 proteins started the entire misfolding process.

This process can only occur in cells infected with SARS-CoV-2 therefore in the presence of the N protein, after this mixed fibril strain is formed and propagates there is no longer a need for the N protein presence. This then creates a 2 stage approach, when these mixed fibrils reach a plateau and a new equilibrium, they stop growing (aggregating), and in this secondary stage these fibrils mixed fibrils start behaving like pure aS fibrils, and at this stage, they have a much higher affinity towards aS monomers aS (aS monomers are proteins that are yet to aggregate and form the fibrils that cascade into complex “misfolded” proteins).

Why is this important you may ask, and the answer is “simple”, what was described here has implications for diseases that are believed to be caused or fueled by misfolded proteins of the synuclein “family” such as Parkinson’s, Lewy bodies dementia, and Multiple System Atrophy, aS is also implicated in the participation of other diseases such as Alzheimer’s.

Of course, this isn’t where this substack ends, superficially this is where orthodoxy and current biological dogma ends, and we delve into one of my insane “ideas”. A friend of this Substack First Contact (also a Substack author) sent me this peculiar news article.

Researchers discover a potential cause of Parkinson’s disease

Researchers at the University of Helsinki have demonstrated that certain strains of Desulfovibrio bacteria are the likely cause of Parkinson’s disease in most cases. The study enables the screening of the carriers of Desulfovibrio strains and the removal of the bacteria from the gut.

Aggregation of alpha-synuclein in a nerve cell. (Image: Timo Myöhänen research group)

“Our findings are significant, as the cause of Parkinson’s disease has gone unknown despite attempts to identify it throughout the last two centuries. The findings indicate that specific strains of Desulfovibrio bacteria are likely to cause Parkinson’s disease. The disease is primarily caused by environmental factors, that is, environmental exposure to the Desulfovibrio bacterial strains that cause Parkinson’s disease. Only a small share, or roughly 10%, of Parkinson’s disease is caused by individual genes,” says Professor Per Saris from the University of Helsinki.

The goal of Professor Saris’s research group was to experimentally investigate whether the Desulfovibrio strains found in patients can result in progress towards Parkinson’s disease.

The principal finding of the group’s recently published study was that these strains in patients with Parkinson’s disease cause aggregation of the α-synuclein protein on a statistically significant level in a model organism for Parkinson’s disease. The worm Caenorhabditis elegans was used as the model organism.

The study also found that Desulfovibrio strains isolated from healthy individuals do not cause α-synuclein aggregation to the same degree. In contrast, the aggregates caused by the Desulfovibrio strains in patients with Parkinson’s diseases were also larger.

“Our findings make it possible to screen for the carriers of these harmful Desulfovibrio bacteria. Consequently, they can be targeted by measures to remove these strains from the gut, potentially alleviating and slowing the symptoms of patients with Parkinson’s disease. Once the Desulfovibrio bacteria are eliminated from the gut, α-synuclein aggregates are no longer formed in intestinal cells, from which they travel towards the brain via the vagus nerve like prion proteins,” Saris sums up.

Original article: 
Desulfovibrio bacteria enhance alpha-synuclein aggregation in a Caenorhabditis
https://doi.org/10.3389/fcimb.2023.1181315

Remarkable finding by the researchers, the group discovered that people suffering from Parkinson’s disease had higher levels of Desulfovibrio bacteria in their guts, and these people had a specific strain of this bacteria and higher levels of it. These strains of Desulfovibrio can form aggregates more severely than others.

After eliminating the Desullovibrio bacteria from the gut, aggregates of aS were no longer formed in intestinal cells, which traveled towards the brain via the vagus nerve, a hitchhiking ride other pathogens also indulge in. This is another important step towards solving the highly complex role of the microbiome, bacteria, and many pathologies, but especially neurodegeneration. While SARS-CoV-2 itself may be able to accelerate both the onset and progression of neurodegenerative, an important and lightly overlooked dynamic is the effect of the infection on the gut microbiome and its persistent effects and impact.

Detection of Intestinal Dysbiosis in Post-COVID-19 Patients One to Eight Months after Acute Disease Resolution

The intestinal microbiota plays an important role in the immune response against viral infections, modulating both innate and adaptive immune responses. The cytokine storm is associated with COVID-19 severity, and the patient’s immune status is influenced by the intestinal microbiota in a gut-lung bidirectional interaction. In this study, we evaluate the intestinal microbiota of Brazilian patients in different post-COVID-19 periods, and correlate this with clinical data and the antibiotic therapy used during the acute phase. DNA extracted from stool samples was sequenced and total anti-SARS-CoV-2 antibodies and C-reactive protein were quantified. Compared with controls, there were significant differences in the microbiota diversity in post-COVID-19 patients, suggesting an intestinal dysbiosis even several months after acute disease resolution. Additionally, we detected some genera possibly associated with the post-COVID-19 dysbiosis, including Desulfovibrio, Haemophillus, Dialister, and Prevotella, in addition to decreased beneficial microbes, associated with antibiotic-induced dysbiosis, such as Bifidobacterium and Akkermansia. Therefore, our hypothesis is that dysbiosis and the indiscriminate use of antibiotics during the pandemic may be associated with post-COVID-19 clinical manifestations. In our study, 39% (n = 58) of patients reported symptoms, including fatigue, dyspnea, myalgia, alopecia, anxiety, memory loss, and depression. These data suggest that microbiota modulation may represent a target for recovery from acute COVID-19 and a therapeutic approach for post-COVID-19 sequelae

Months after acute COVID infection, they found patients suffered from dysbiosis, with a severe shift in the microbiome, with certain microbes overpopulation the gut, while beneficial ones decreased significantly. One of the microbes that increase in abundance is Desulfovibrio, the same one that we just found out can be responsible for Parkinson’s Disease and aS-related pathologies.

This isn’t a novel dynamic by the virus, even the “milder” Omicron variant causes a shift in the microbiome displacing Akkermansia months after the “mild infection”, and Akkermansia is responsible for many, many positive effects in the body, from maintaining proper glucose metabolism to protecting from many diseases, one of them being Alzheimer’s disease.

The role of SARS-CoV-2, the Spike Protein in many diseases will be incredibly complex to untangle, but at the core of the dynamics will lie certain “novel” behaviors. When I and a friend were researching and reverse engineering the mRNA vaccine, nothing on its own could quite explain everything we were seeing, neither what we knew about the Spike Protein so far, the chemical makeup of the mRNA (LNPs), nor anything else, this was when I started exploring the potential role of Endotoxins and its possible interactions with the Spike Protein, proven last year to be a fact. Next, we explored the roles of biofilms in creating viral reservoirs among its many other capabilities, this role has yet to be proven, but it has been proposed and demonstrated the Spike Protein interacts and “bursts” with biofilms.

Now this is where things get a little… outlandish. Given how the Spike interacts with bacteria, endotoxins, and biofilms, translocating bacteria in the body, and causing increased fungal infections, I and my friend thought misfolded proteins are not merely pathologic, but perhaps a forgotten defense mechanism, a last-ditch recourse by the body, similar to autoantibodies.

Amyloid-Beta, believe to be considered the driving force behind many neurodegenerative diseases is an antimicrobial peptide (another source) being able to trap and kill pathogens. A similar role for Alpha-Synuclein has been discovered, in this paper the researchers demonstrated its antibacterial activity against E. Coli, and Staphylococcus Aureus, and also inhibiting fungal strains such as Aspergillus Flavus, Fumigatus, and Rhizoctonia Solani. The following, from here.

Most remarkably αS is trafficked to the central nervous system (CNS) conferring immunity in advance of an infection. Chronic GI infection or breakdown of the epithelial barrier can cause αS to accumulate and form neurotoxic aggregates.

My focus on Endotixin and LPS and its whole on the overall effects of everything discussed is less of a bias and more of a complexity awareness perspective. When LPS is associated with Aβ_{1-42 (the antimicrobial sequence in amyloid)} creates a loop, Aβ_1-42 is an agonist (makes the body produce more of something) for TLR4 receptors, which are the main receptor for LPS.

At the core of many of the long-term effects of the virus and Spike Protein (especially mRNA/Adenovirus Spike) lies these interactions I just described in a few paragraphs above. Being able to interact with bacteria, and biofilms, and heavily tilt the microbiome towards dysbiosis all play a significant role in long-term disease, alongside many other aspects we covered. The following piece is more of a collage and brief explanation of the complexity of biofilms rather than my usual substacks, still pertinent to this day.

PAID - Into the chasm

The N protein-aS is very important information since many millions of people globally have been slowly developing immunity towards this protein, which entails the effects we just analyzed as being more present and more possible, as I wrote days ago, the body has very few ways to deal with unwanted proteins if it can’t get “rid” of it, and misfolding proteins into inflammatory or “aggressive” proteins is one of them.

Of course, this is mostly talking about the S1 of the Spike, there are many secrets in the S2, yet to be uncovered.

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