| First Author | Taguchi YV | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 40 | Pages | 9617-9631 |
| PubMed ID | 28847804 | Mgi Jnum | J:253020 |
| Mgi Id | MGI:6095024 | Doi | 10.1523/JNEUROSCI.1525-17.2017 |
| Citation | Taguchi YV, et al. (2017) Glucosylsphingosine Promotes alpha-Synuclein Pathology in Mutant GBA-Associated Parkinson's Disease. J Neurosci 37(40):9617-9631 |
| abstractText | 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 alpha-synuclein aggregation in vitro, glucosylsphingosine triggers the formation of oligomeric alpha-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 alpha-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 alpha-synuclein pathology. These findings indicate that glucosylsphingosine promotes pathological aggregation of alpha-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. |
