Altered protein folding leading to the formation of structured aggregates such as amyloid fibrils has gained significant attention due to its association with neurodegenerative diseases. α-Synuclein, a small intrinsically disordered protein, gets transformed into amyloid fibrils under unfavorable conditions and contributes to the progression and pathology of Parkinson's disease (PD). Under normal physiological conditions, amyloid formation is controlled by many chaperones and chaperone-like proteins. However, with aging, the protein homeostasis machinery becomes less efficient, causing the loss of proper functioning of chaperones and leading to aberrant protein folding and amyloid formation. Here, we provide in-depth information on the modulation of α-synuclein amyloid assembly by a heterogeneous complex of bovine eye lens protein, α-crystallin, which is known to possess chaperone-like activity. We have used a multiparametric approach to discern the critical events through which α-crystallin abolishes α-synuclein amyloid formation. Our biochemical and biophysical data analysis revealed that α-crystallin, at substoichiometric ratios, alleviates α-synuclein amyloid assembly and drives it into soluble dead-end intermediates. We also demonstrated that α-crystallin was equally efficient in arresting amyloid assembly by some of the PD-related mutants suggesting the significance of chaperone-like activity of α-crystallin under pathological conditions. Finally, we validated our results using human crystallin derived from cataract patients. Based on our findings, we propose that the interaction of α-crystallin directs α-synuclein into a soluble amyloid-incompetent form. Our results suggest that the generic antiamyloid property of chaperone-like proteins, such as α-crystallin, can be harnessed to design protein and peptide-based novel therapeutics for prevention and treatment of deadly neurodegenerative diseases.
Keywords: Parkinson’s disease; amyloid fibrils; chaperone-like proteins; inhibition; α-crystallin; α-synuclein.