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, Joe Mazzulli*

*Corresponding author for this work

Research output: Contribution to journalArticle

29 Citations (Scopus)

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

Fingerprint

Synucleins
Glucosylceramides
Glycosphingolipids
Poisons
Parkinson Disease
Dopaminergic Neurons
Mesencephalon
Glucosylceramidase
Pathology
Gaucher Disease
Mutation
Reducing Agents
Synapses
Molecular Weight
Neurons

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)

Cite this

Zunke, F., Moise, A. C., Belur, N. R., Gelyana, E., Stojkovska, I., Dzaferbegovic, H., ... Mazzulli, J. (2018). Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron, 97(1), 92-107.e10. https://doi.org/10.1016/j.neuron.2017.12.012
Zunke, Friederike ; Moise, Alexandra C. ; Belur, Nandkishore R. ; Gelyana, Eilrayna ; Stojkovska, Iva ; Dzaferbegovic, Haris ; Toker, Nicholas J. ; Jeon, Sohee ; Fredriksen, Kristina ; Mazzulli, Joe. / Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide. In: Neuron. 2018 ; Vol. 97, No. 1. pp. 92-107.e10.
@article{6e1f2ddadd9644259b3cfe3227378c2d,
title = "Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide",
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.",
keywords = "GBA1, Gaucher disease, Lewy body, Parkinson's disease, glucocerebrosidase, iPS-derived dopaminergic neurons, lysosomal storage disease, protein aggregation, α-synuclein",
author = "Friederike Zunke and Moise, {Alexandra C.} and Belur, {Nandkishore R.} and Eilrayna Gelyana and Iva Stojkovska and Haris Dzaferbegovic and Toker, {Nicholas J.} and Sohee Jeon and Kristina Fredriksen and Joe Mazzulli",
year = "2018",
month = "1",
day = "3",
doi = "10.1016/j.neuron.2017.12.012",
language = "English (US)",
volume = "97",
pages = "92--107.e10",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "1",

}

Zunke, F, Moise, AC, Belur, NR, Gelyana, E, Stojkovska, I, Dzaferbegovic, H, Toker, NJ, Jeon, S, Fredriksen, K & Mazzulli, J 2018, 'Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide', Neuron, vol. 97, no. 1, pp. 92-107.e10. https://doi.org/10.1016/j.neuron.2017.12.012

Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide. / Zunke, Friederike; Moise, Alexandra C.; Belur, Nandkishore R.; Gelyana, Eilrayna; Stojkovska, Iva; Dzaferbegovic, Haris; Toker, Nicholas J.; Jeon, Sohee; Fredriksen, Kristina; Mazzulli, Joe.

In: Neuron, Vol. 97, No. 1, 03.01.2018, p. 92-107.e10.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide

AU - Zunke, Friederike

AU - Moise, Alexandra C.

AU - Belur, Nandkishore R.

AU - Gelyana, Eilrayna

AU - Stojkovska, Iva

AU - Dzaferbegovic, Haris

AU - Toker, Nicholas J.

AU - Jeon, Sohee

AU - Fredriksen, Kristina

AU - Mazzulli, Joe

PY - 2018/1/3

Y1 - 2018/1/3

N2 - 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.

AB - 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.

KW - GBA1

KW - Gaucher disease

KW - Lewy body

KW - Parkinson's disease

KW - glucocerebrosidase

KW - iPS-derived dopaminergic neurons

KW - lysosomal storage disease

KW - protein aggregation

KW - α-synuclein

UR - http://www.scopus.com/inward/record.url?scp=85040558820&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85040558820&partnerID=8YFLogxK

U2 - 10.1016/j.neuron.2017.12.012

DO - 10.1016/j.neuron.2017.12.012

M3 - Article

VL - 97

SP - 92-107.e10

JO - Neuron

JF - Neuron

SN - 0896-6273

IS - 1

ER -

Zunke F, Moise AC, Belur NR, Gelyana E, Stojkovska I, Dzaferbegovic H et al. Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 2018 Jan 3;97(1):92-107.e10. https://doi.org/10.1016/j.neuron.2017.12.012