Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide
Copyright © 2017 Elsevier Inc. All rights reserved..
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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2018 |
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| Erschienen: |
2018 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:97 |
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| Enthalten in: |
Neuron - 97(2018), 1 vom: 03. Jan., Seite 92-107.e10 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zunke, Friederike [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 05.07.2019 Date Revised 09.04.2022 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.neuron.2017.12.012 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM279539002 |
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| 520 | |a Copyright © 2017 Elsevier Inc. All rights reserved. | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a GBA1 | |
| 650 | 4 | |a Gaucher disease | |
| 650 | 4 | |a Lewy body | |
| 650 | 4 | |a Parkinson’s disease | |
| 650 | 4 | |a glucocerebrosidase | |
| 650 | 4 | |a iPS-derived dopaminergic neurons | |
| 650 | 4 | |a lysosomal storage disease | |
| 650 | 4 | |a protein aggregation | |
| 650 | 4 | |a α-synuclein | |
| 650 | 7 | |a Glucosylceramides |2 NLM | |
| 650 | 7 | |a Glycosphingolipids |2 NLM | |
| 650 | 7 | |a alpha-Synuclein |2 NLM | |
| 700 | 1 | |a Moise, Alexandra C |e verfasserin |4 aut | |
| 700 | 1 | |a Belur, Nandkishore R |e verfasserin |4 aut | |
| 700 | 1 | |a Gelyana, Eilrayna |e verfasserin |4 aut | |
| 700 | 1 | |a Stojkovska, Iva |e verfasserin |4 aut | |
| 700 | 1 | |a Dzaferbegovic, Haris |e verfasserin |4 aut | |
| 700 | 1 | |a Toker, Nicholas J |e verfasserin |4 aut | |
| 700 | 1 | |a Jeon, Sohee |e verfasserin |4 aut | |
| 700 | 1 | |a Fredriksen, Kristina |e verfasserin |4 aut | |
| 700 | 1 | |a Mazzulli, Joseph R |e verfasserin |4 aut | |
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