Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide
| Autor: | Sohee Jeon, Friederike Zunke, Eilrayna Gelyana, Nicholas J. Toker, Iva Stojkovska, Kristina Fredriksen, Nandkishore R. Belur, Haris Dzaferbegovic, Alexandra C. Moise, Joseph R. Mazzulli |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Parkinson's disease Reducing agent animal diseases Protein aggregation Glucosylceramides Glycosphingolipids Article 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Dopamine Mesencephalon medicine Lysosomal storage disease Humans Conformational isomerism Cells Cultured General Neuroscience Dopaminergic Neurons Parkinson Disease Glycosphingolipid medicine.disease nervous system diseases 030104 developmental biology chemistry nervous system Biophysics alpha-Synuclein lipids (amino acids peptides and proteins) Glucocerebrosidase 030217 neurology & neurosurgery medicine.drug |
| Zdroj: | Neuron. 97(1) |
| ISSN: | 1097-4199 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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