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J Neurosci. 2017 Oct 4;37(40):9617-9631. doi: 10.1523/JNEUROSCI.1525-17.2017. Epub 2017 Aug 28.

Glucosylsphingosine Promotes α-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease.

Author information

1
Department of Cell Biology.
2
Program in Cellular Neuroscience, Neurodegeneration and Repair.
3
Department of Internal Medicine.
4
Sanofi Genzyme, Framingham, Massachusetts 01702.
5
Department of Neurology, and.
6
Department of Internal Medicine, pramod.mistry@yale.edu sreeganga.chandra@yale.edu.
7
Program in Cellular Neuroscience, Neurodegeneration and Repair, pramod.mistry@yale.edu sreeganga.chandra@yale.edu.
8
Department of Neuroscience, Yale University School of Medicine, New Haven, Connecticut 06519, and.

Abstract

Glucocerebrosidase 1 (GBA) mutations responsible for Gaucher disease (GD) are the most common genetic risk factor for Parkinson's disease (PD). Although the genetic link between GD and PD is well established, the underlying molecular mechanism(s) are not well understood. We propose that glucosylsphingosine, a sphingolipid accumulating in GD, mediates PD pathology in GBA-associated PD. We show that, whereas GD-related sphingolipids (glucosylceramide, glucosylsphingosine, sphingosine, sphingosine-1-phosphate) promote α-synuclein aggregation in vitro, glucosylsphingosine triggers the formation of oligomeric α-synuclein species capable of templating in human cells and neurons. Using newly generated GD/PD mouse lines of either sex [Gba mutant (N370S, L444P, KO) crossed to α-synuclein transgenics], we show that Gba mutations predispose to PD through a loss-of-function mechanism. We further demonstrate that glucosylsphingosine specifically accumulates in young GD/PD mouse brain. With age, brains exhibit glucosylceramide accumulations colocalized with α-synuclein pathology. These findings indicate that glucosylsphingosine promotes pathological aggregation of α-synuclein, increasing PD risk in GD patients and carriers.SIGNIFICANCE STATEMENT Parkinson's disease (PD) is a prevalent neurodegenerative disorder in the aging population. Glucocerebrosidase 1 mutations, which cause Gaucher disease, are the most common genetic risk factor for PD, underscoring the importance of delineating the mechanisms underlying mutant GBA-associated PD. We show that lipids accumulating in Gaucher disease, especially glucosylsphingosine, play a key role in PD pathology in the brain. These data indicate that ASAH1 (acid ceramidase 1) and GBA2 (glucocerebrosidase 2) enzymes that mediate glucosylsphingosine production and metabolism are attractive therapeutic targets for treating mutant GBA-associated PD.

KEYWORDS:

GBA; glucosylsphingosine; α-synuclein

PMID:
28847804
PMCID:
PMC5628407
DOI:
10.1523/JNEUROSCI.1525-17.2017
[Indexed for MEDLINE]
Free PMC Article

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