Fig. 1.

a Pathologically toxic species in the α-synuclein aggregation pathway. α-Synuclein polypeptide transforms from physiological monomeric helical state to misfolded monomers, leading to the formation of small and large oligomers and finally stack as fibrils, which accumulate in cell in the form of Lewy bodies. The least compact oligomeric species are reported to be the most toxic by affecting a number of cellular processes to disrupt cellular functions [27, 33]. Fibrils are not as toxic as oligomers but there quantitative presence in the cell interferes with the normal cellular functions and ultimately leads to neuronal loss. b Role of chaperones in maintaining α-synuclein protein homeostasis. Molecular chaperones act on misfolded α-synuclein monomers which are cytotoxic in two ways: first, they unfold them back to a natively foldable conformation as assisted by Hsp70 and co-chaperones. Second, they may prevent α-synuclein misfolding and aggregation by mere “holding”, as in the case of the small heat shock proteins [70, 130, 162]. Further, already formed stable small oligomeric α-synuclein aggregates, which are toxic can become disaggregated and unfolded by the Hsp104 + Hsp70 + Hsp40 chaperone machinery or in the human cytosol by the Hsp110 + Hsp70 + Hsp40 chaperone machinery and disaggregated into monomers that may reach their harmless native state [91, 96, 109, 163]