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Biomacromolecules. 2018 Apr 9;19(4):1118-1129. doi: 10.1021/acs.biomac.7b01727. Epub 2018 Mar 26.

Extracellular α-Synuclein Disrupts Membrane Nanostructure and Promotes S-Nitrosylation-Induced Neuronal Cell Death.

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Functional Proteomics Laboratory , Regional Centre for Biotechnology (RCB) , NCR Biotech Science Cluster, third Milestone Gurgaon-Faridabad Expressway , Faridabad , 121001 , India.
Manipal Academy of Higher Education , Manipal , Karnataka 576104 , India.
KIIT University , Bhubaneswar , Odisha India.


α-Synuclein, a major constituent of proteinaceous inclusions named Lewy body, has been shown to be released and taken up by cells, which may facilitate its progressive pathological spreading and neuronal cell death in Parkinson's disease. However, the pathophysiological effect and signaling cascade initiated by extracellular α-synuclein in cellular milieu are not well understood. Herein we have investigated the perturbations induced by low molecular weight α-synuclein and different types of α-synuclein oligomers in the neuroblastoma SH-SY5Y cells. Atomic force microscopy studies have revealed formation of nanopores and enhanced roughness in the cell surface leading to membrane disruption. The damaged membrane allows altered ionic homeostasis leading to activation of nitric oxide synthase (NOS) machinery releasing burst of nitric oxide. The elevated levels of nitric oxide induces S-nitrosylation of key proteins like Actin, DJ-1, HSP70 UCHL1, Parkin, and GAPDH that alter cytoskeletal network, protein folding machinery, ubiquitin proteasome system inducing apoptosis.


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