| Literature DB >> 29290548 |
Friederike Zunke1, Alexandra C Moise1, Nandkishore R Belur1, Eilrayna Gelyana1, Iva Stojkovska1, Haris Dzaferbegovic1, Nicholas J Toker1, Sohee Jeon1, Kristina Fredriksen1, Joseph R Mazzulli2.
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.Entities:
Keywords: GBA1; Gaucher disease; Lewy body; Parkinson’s disease; glucocerebrosidase; iPS-derived dopaminergic neurons; lysosomal storage disease; protein aggregation; α-synuclein
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Year: 2017 PMID： 29290548 PMCID： PMC6013314 DOI： 10.1016/j.neuron.2017.12.012
Source DB: PubMed Journal: Neuron ISSN： 0896-6273 Impact factor: 17.173