COVID-19 Protein Found to Speed Toxic Alpha-Synuclein Buildup

Patricia Inácio, PhD avatar

by Patricia Inácio, PhD |

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A protein present in the SARS-CoV-2 virus — the virus that causes COVID-19 — is able to interact with alpha-synuclein and speed the formation of amyloid fibrils, the toxic clumps that trigger nerve cells death and are a hallmark of Parkinson’s disease, a study has shown.

“We show, in test tube experiments, that … SARS-CoV-2 nucleocapsid protein (N-protein) considerably speeds up the aggregation process,” the researchers wrote. N-protein is one of the virus’ two most abundant proteins.

These findings highlight the potential long-term implications of COVID-19 and could help explain a possible link between COVID-19 and Parkinson’s disease, according to researchers.

The study, “Interactions between SARS-CoV-2 N-Protein and α-Synuclein Accelerate Amyloid Formation,” was published in the journal ACS Chemical Neuroscience.

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Infection with SARS-CoV-2 affects primarily the lungs but also other organs, including the brain. As a result, some patients have reported neurological symptoms, including headaches, “brain fog” and loss of smell — also a common early non-motor symptom of Parkinson’s disease.

However, whether these symptoms are triggered by the virus once it reaches the brain, or are instead a consequence of the immune system’s reaction remains controversial.

Recent case reports of relatively young people who developed Parkinson’s after contracting COVID-19 suggest a potential link between both diseases.

Now, a team of researchers investigated whether protein components of the SARS-CoV-2 virus that causes COVID-19 could trigger the formation of toxic protein clumps called amyloid fibrils. A hallmark of Parkinson’s disease, the key component of these clumps is the alpha-synuclein protein.

Researchers studied the two most abundant proteins in the virus: the spike (S-) protein that helps the virus enter cells, and the nucleocapsid (N-) protein that composes the viral capsid (shell) with its genomic information.

In vitro or laboratory tests were conducted in which the amyloid fibrils were linked to a fluorescent probe to make them visible and easy to track.

In the absence of any COVID-19-related viral protein, the alpha-synuclein protein took more than 240 hours — longer than 10 days — to aggregate into amyloid fibrils. No new effects were seen when the researchers added the viral S-protein.

However, with the viral N-protein, the team found that alpha-synuclein formed fibrils in less than 24 hours, or within one day.

“In the presence of N-protein, the onset of [alpha-synuclein] aggregation into amyloid fibrils is strongly accelerated, indicating that N-protein facilitates the formation of a critical nucleus for aggregation,” the researchers wrote.

Further experiments showed that the viral N-protein and alpha-synuclein interacted directly, with at least three to four copies of alpha-synuclein bound to each N-protein.

Next, human neural cells called SH-SY5Y, a standard cellular model to study neurodegenerative disorders, were injected with the N-protein and fluorescently labeled alpha-synuclein. The N-protein was injected at a concentration similar to that expected inside a SARS-CoV-2-infected cell.

The rate of dead cells was double for those that had received both proteins compared with cells that were injected with alpha-synuclein alone and that served as controls.

The distribution of alpha-synuclein was also different, with cells injected with both proteins showing more elongated, fibril-like structures. The researchers, however, could not confirm that they were amyloid fibrils.

Overall, “our results point toward a direct interaction between the N-protein of SARS-CoV-2 and αS [alpha-synuclein] as a molecular basis for the observed relations between virus infections and Parkinsonism,” the researchers wrote.

These interactions “suggest that SARS-CoV-2 infections may have long-term implications and that caution is required in considering N-protein as an alternative target in vaccination strategies,” they added.