@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 Mazzulli, {Joseph R.}",
note = "Funding Information: We thank Peter T. Lansbury, Jr. (Harvard Medical School), Dimitri Krainc (Northwestern University), Christopher M. Dobson (University of Cambridge), and Celine Galvagnion (DZNE) for helpful discussions. We thank Michela Deleidi and Thomas Gasser (University of T{\"u}bingen) for generously providing the L444P iPSC line and Rakez Kayed (University of Texas Medical Branch) for generously providing the A11 antibody. Lipid measurements were supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina (P30 CA138313) and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department of Biochemistry, Medical University of South Carolina (P20 RR017677). This research was supported by the National Institute of Neurological Disorders and Stroke grant R01NS092823 (J.R.M.), Northwestern PDMD Advisory Council (J.R.M.), the Michael J. Fox Foundation (grant ID 12158 to J.R.M.), and the Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University and NIH core support grant P30 NS081774. Funding Information: We thank Peter T. Lansbury, Jr. (Harvard Medical School), Dimitri Krainc (Northwestern University), Christopher M. Dobson (University of Cambridge), and Celine Galvagnion (DZNE) for helpful discussions. We thank Michela Deleidi and Thomas Gasser (University of T{\"u}bingen) for generously providing the L444P iPSC line and Rakez Kayed (University of Texas Medical Branch) for generously providing the A11 antibody. Lipid measurements were supported in part by the Lipidomics Shared Resource, Hollings Cancer Center, Medical University of South Carolina ( P30 CA138313 ) and the Lipidomics Core in the South Carolina Lipidomics and Pathobiology Center of Biomedical Research Excellence, Department of Biochemistry, Medical University of South Carolina ( P20 RR017677 ). This research was supported by the National Institute of Neurological Disorders and Stroke grant R01NS092823 (J.R.M.), Northwestern PDMD Advisory Council (J.R.M.), the Michael J. Fox Foundation (grant ID 12158 to J.R.M.), and the Human Embryonic and Induced Pluripotent Stem Cell Facility at Northwestern University and NIH core support grant P30 NS081774 . Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",
year = "2018",
month = jan,
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",
}
