Cytotoxic Oligomers and Fibrils Trapped in a Gel-like State of α-Synuclein Assemblies.

Autor: Kumar R; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India., Das S; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India.; IITB-Monash Research Academy, IIT Bombay, Powai, Mumbai, 400076, India., Mohite GM; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India., Rout SK; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India., Halder S; TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Sy. No. 36/P, Gopanpally, Ranga Reddy District, Hyderabad, 500 017, India., Jha NN; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India., Ray S; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India., Mehra S; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India., Agarwal V; TIFR Centre for Interdisciplinary Sciences, Tata Institute of Fundamental Research, Sy. No. 36/P, Gopanpally, Ranga Reddy District, Hyderabad, 500 017, India., Maji SK; Department of Biosciences and Bioengineering, IIT Bombay, Powai, Mumbai, 400076, India.
Jazyk: angličtina
Zdroj: Angewandte Chemie (International ed. in English) [Angew Chem Int Ed Engl] 2018 May 04; Vol. 57 (19), pp. 5262-5266. Date of Electronic Publication: 2018 Apr 14.
DOI: 10.1002/anie.201711854
Abstrakt: α-Synuclein (α-Syn) aggregation is associated with Parkinson's disease (PD) pathogenesis. In PD, the role of oligomers versus fibrils in neuronal cell death is debatable, but recent studies suggest oligomers are a proximate neurotoxin. Herein, we show that soluble α-Syn monomers undergo a transformation from a solution to a gel state on incubation at high concentration. Detailed characterization of the gel showed the coexistence of monomers, oligomers, and short fibrils. In vitro, the gel was highly cytotoxic to human neuroblastoma cells. The individual constituents of the gel are short-lived species but toxic to the cells. They comprise a structurally heterogeneous population of α-helical and β-sheet-rich oligomers and short fibrils with the cross-β motif. Given the recent evidence of the gel-like state of the protein associated with neurodegenerative diseases, the gel state of α-Syn in this study represents a mechanistic and structural model for the in vivo toxicity of α-Syn in PD.
(© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
Databáze: MEDLINE
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