A comprehensive mini-review on amyloidogenesis of different SARS-CoV-2 proteins and its effect on amyloid formation in various host proteins

Abstract

Amyloidogenesis is the inherent ability of proteins to change their conformation from native state to cross β-sheet rich fibrillar structures called amyloids which result in a wide range of diseases like Parkinson's disease, Alzheimer's disease, Finnish familial amyloidosis, ATTR amyloidosis, British and Danish dementia, etc. COVID-19, on the other hand is seen to have many similarities in symptoms with other amyloidogenic diseases and the overlap of these morbidities and symptoms led to the proposition whether SARS-CoV-2 proteins are undergoing amyloidogenesis and whether it is resulting in or aggravating amyloidogenesis of any human host protein. Thus the SARS-CoV-2 proteins in infected cells, i.e., Spike (S) protein, Nucleocapsid (N) protein, and Envelope (E) protein were tested via different machinery and amyloidogenesis in them were proven. In this review, we will analyze the pathway of amyloid formation in S-protein, N-protein, E-protein along with the effect that SARS-CoV-2 is creating on various host proteins leading to the unexpected onset of many morbidities like COVID-induced Acute Respiratory Distress Syndrome (ARDS), Parkinsonism in young COVID patients, formation of fibrin microthrombi in heart, etc., and their future implications.

Keywords: ARDS; ATTR; Amyloidogenesis; COVID-19; Envelope protein; Nucleocapsid protein; Serum amyloid A; Spike protein; α-Synuclein.

Fig. 1

Graphical representation of the SARS-CoV-2 protein undergoing/accelerating amyloidogenesis; A S-protein digested by serine protease enzyme like neutrophil esterase results in formation of amyloid-prone segment 193–202 which later forms amyloids; B N-protein (left) interacts with amyloidogenic α-Synuclein protein (right) and results in acceleration of amyloidogenesis; C E-protein destabilizes by hydrophobic interaction with the environment into nine-residue segment TK9 which forms amyloids by self-assembly

Fig. 2

Aggregation of αS in the absence and presence of SARS-CoV-2 proteins. a Aggregation assay of αS in the absence (black) and presence (color) of S-protein. The aggregation process is followed by recording the fluorescence of the amyloid-binding dye ThT. The assay was performed at a NaCl concentration of 10 mM with 50 μM αS and 0.1 μM (red), 0.5 μM (orange), and 1 μM (blue) S-protein. b ThT-based aggregation assay of αS in the presence of N-protein. The assay was performed at a salt concentration of 10 mM NaCl with 50 μM αS and 0 μM (black) 0.1 μM (red), 0.5 μM (orange), 0.8 μM (green) and 1 μM (blue) N-protein. c Influence of the salt concentration on aggregation lag time for N-protein concentrations of 0.5 μM (orange), 0.8 μM (green) and 1 μM (blue) at an αS concentration of 50 μM. The points represent the mean of three independent measurements, and error bars show the standard deviation. Figure taken with permission from Ref. (Semerdzhiev et al. 2022)

Fig. 3

Graphical representation of effect of SARS-CoV-2 on pre-existing Amyloidogenic entities in our body; A Fluid-filled alveoli (left) of ARDS affected patient when comes under effect pf COVID-19 results in increased propensity of amyloidosis; B Downregulation of ACE-2 and upregulation of S-protein in lungs post-COVID infection leads to formation of amyloidic microclots in pulmonary vasculature; C Native serum amyloid-A hexamer undergoes several pathways in presence of nine-residue segment of E-protein called SK9 and ultimately leads to amyloid fibril formation; All these results finally culminates into one outcome, i.e., aggravation of COVID-like symptoms and severity of co-morbidities

Fig. 4

The possible pathways of amyloid formation in severe acute respiratory syndrome coronavirus-2/coronavirus disease-2019 (SARS-CoV-2/ COVID-19)-induced acute respiratory distress syndrome (ARDS). Figure taken with permission from Ref. (Sinha and Thakur 2021)