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

Friederike Zunke, Alexandra C. Moise, Nandkishore R. Belur, Eilrayna Gelyana, Iva Stojkovska, Haris Dzaferbegovic, Nicholas J. Toker, Sohee Jeon, Kristina Fredriksen, Joseph R. Mazzulli*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

63 Scopus citations

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. Zunke et al. found that glycosphingolipids that accumulate in Gaucher disease cause a reversible structural change in Parkinson's protein α-synuclein, promoting its aggregation and toxicity. In patient-derived midbrain dopamine neurons, glycosphingolipid reduction restored physiological α-synuclein conformers and diminished pathology.

Original languageEnglish (US)
Pages (from-to)92-107.e10
JournalNeuron
Volume97
Issue number1
DOIs
StatePublished - Jan 3 2018

Keywords

  • GBA1
  • Gaucher disease
  • Lewy body
  • Parkinson's disease
  • glucocerebrosidase
  • iPS-derived dopaminergic neurons
  • lysosomal storage disease
  • protein aggregation
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)

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