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Glucosylsphingosine promotes α-synuclein pathology in mutant GBA-associated Parkinson's disease.

著者 Taguchi YV , Liu J , Ruan J , Pacheco J , Zhang X , Abbasi J , Keutzer J , Mistry PK , Chandra SS
J Neurosci.2017 Aug 28 ; ():.
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Glucocerebrosidase 1 (GBA) mutations responsible for Gaucher disease (GD) are the most common genetic risk factor for Parkinson's disease (PD). While 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 while 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, knockout) 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 co-localized with α-synuclein pathology. These findings indicate that glucosylsphingosine promotes pathological aggregation of α-synuclein, increasing PD risk in GD patients and carriers.SIGNIFICANCE STATEMENTParkinson's disease (PD) is a prevalent neurodegenerative disorder in the ageing population. Glucocerebrosidase 1 mutations which cause Gaucher disease (GD) 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 GD, especially glucosylsphingosine, play a key role in PD pathology in the brain. These data indicate that ASAH1 (acid ceramidase1) and GBA2 (Glucocerebrosidase 2) enzymes that mediate glucosylsphingsoine production and metabolism are attractive therapeutic targets for treating mutant GBA-associated PD.
PMID: 28847804 [PubMed - as supplied by publisher]
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