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.
Pubmed ID: 29290548 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.
View all literature mentionsSoftware for image processing, analysis, and editing. The software includes features such as touch capabilities, a customizable toolbar, 2D and 3D image merging, and Cloud access and options.
View all literature mentionsMolecular biology software for visualizing and documenting gene constructs for InFusion cloning, Gibson assembly, restriction cloning, PCR, and mutagenesis.
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets IgG
View all literature mentionsThis monoclonal targets Tyrosine Hydroxylase antibody produced in mouse
View all literature mentionsThis unknown targets Synapsin 1
View all literature mentionsThis monoclonal targets Neuronal Class III beta-Tubulin (TUJ1) Purified
View all literature mentionsThis monoclonal targets Neurofilament Marker
View all literature mentionsThis monoclonal targets GADPH
View all literature mentionsThis monoclonal targets alpha-Tubulin antibody produced in mouse
View all literature mentionsThis monoclonal targets Human a-Synuclein
View all literature mentionsThis monoclonal targets alpha Synuclein
View all literature mentionsThis monoclonal targets alpha Synuclein
View all literature mentionsThis monoclonal targets alpha-Synuclein
View all literature mentionsThis polyclonal targets SNCA
View all literature mentionsThis monoclonal targets alpha Synuclein antibody [LB 509]
View all literature mentions