Cytotoxic aggregates of SARS-CoV-2 proteins may trigger neurologic symptoms in patients with COVID-19, according to study findings published in Nature Communications.
Although COVID-19 is known primarily as a respiratory disease that is caused by infection with SARS-CoV-2, such neurologic symptoms as memory loss, severe headaches, sensory confusion, and stroke have been reported in up to 30% of patients, which can persist even after the infection is over (ie, long COVID). It is thought that these neurologic symptoms are induced by the virus infecting the central nervous system (CNS), but the molecular mechanisms that trigger these symptoms have not yet been elucidated.
Recognizing that the neurologic effects of COVID-19 share similarities with neurodegenerative diseases in which the presence of cytotoxic-aggregated amyloid protein or peptides is a common feature, the researchers sought to evaluate whether some neurologic symptoms of COVID-19 may also follow an amyloid etiology. In their analysis, they focused on a selection of proteins from the SARS-CoV-2 proteome, which are known as the open reading frames (ORFs). They conducted a bioinformatics screening of the ORF proteins in an attempt to locate potential amyloidogenic peptide sequences. The analysis was utilized to choose 2 subsequences — 1 each from ORF6 and ORF10 — for synthesis.
Both of the synthesized peptides were found to rapidly self-assemble into amyloid assemblies with a variety of polymorphic morphologies, the researchers explained. They further explained cytotoxicity assays on neuronal cell lines revealed peptide assemblies to be highly toxic at concentrations as low as .0005% (0.04 mg/mL–1). Additionally, the amyloids were shown to be highly toxic to neuronal cells.
To further assess the polymorphic nature of the assembly of these peptides, the researchers examined the structures formed from 1:1 mixtures of the 2 peptides. When mixed prior to assembly, “the peptides form a wide range of polymorphic structures exceeding that of either peptide assembled individually.” These well-ordered 2D structures revealed were never observed with either of the peptides individually, thus providing clear-cut evidence of co-crystallization.
The investigators concluded that “it is entirely plausible that amyloid assemblies either from these ORF proteins or other viral proteins could be present in the CNS of COVID-19 patients.”
The cytotoxicity and protease-resistant structure of these assemblies may be associated with their persistent presence in the CNS of patients postinfection, which might explain, in part, the lasting neurologic symptoms of COVID-19, particularly those that are novel relative to other postviral syndromes — for example, that following the original SARS-CoV-1 infection. Based on the typically slow progress of neurodegenerative diseases, if such a trend does exist, it will most likely take some time to become evident epidemiologically.
Disclosure: None of the study authors has declared affiliations with biotech, pharmaceutical, and/or device companies.
Charnley M, Islam S, Bindra GK, et al. Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms inCOVID-19. Nat Commun. Published online June 13, 2022. doi:10.1038/s41467-022-30932-1