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      Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide

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          Abstract

          α-Synuclein (α-syn) aggregation is a key event in Parkinson's disease (PD). Mutations in glycosphingolipid (GSL)-degrading glucocerebrosidase are risk factors for PD, indicating that disrupted GSL clearance plays a key role in α-syn aggregation. However, the mechanisms of GSL-induced aggregation are not completely understood. We document the presence of physiological α-syn conformers in human midbrain dopamine neurons and tested their contribution to the aggregation process. Pathological α-syn assembly mainly occurred through the conversion of high molecular weight (HMW) physiological α-syn conformers into compact, assembly-state intermediates by glucosylceramide (GluCer), without apparent disassembly into free monomers. This process was reversible in vitro through GluCer depletion. Reducing GSLs in PD patient neurons with and without GBA1 mutations diminished pathology and restored physiological α-syn conformers that associated with synapses. Our work indicates that GSLs control the toxic conversion of physiological α-syn conformers in a reversible manner that is amenable to therapeutic intervention by GSL reducing agents.

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          Author and article information

          Journal
          Neuron
          Neuron
          Elsevier BV
          08966273
          January 2018
          January 2018
          : 97
          : 1
          : 92-107.e10
          Article
          10.1016/j.neuron.2017.12.012
          6013314
          29290548
          cb027597-7c2b-48f0-ab16-1b7edb2e7e25
          © 2018

          https://www.elsevier.com/tdm/userlicense/1.0/

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