| First Author | Uemura N | Year | 2015 |
| Journal | PLoS Genet | Volume | 11 |
| Issue | 4 | Pages | e1005065 |
| PubMed ID | 25835295 | Mgi Jnum | J:224707 |
| Mgi Id | MGI:5688810 | Doi | 10.1371/journal.pgen.1005065 |
| Citation | Uemura N, et al. (2015) Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. PLoS Genet 11(4):e1005065 |
| abstractText | Homozygous mutations in the glucocerebrosidase (GBA) gene result in Gaucher disease (GD), the most common lysosomal storage disease. Recent genetic studies have revealed that GBA mutations confer a strong risk for sporadic Parkinson's disease (PD). To investigate how GBA mutations cause PD, we generated GBA nonsense mutant (GBA-/-) medaka that are completely deficient in glucocerebrosidase (GCase) activity. In contrast to the perinatal death in humans and mice lacking GCase activity, GBA-/- medaka survived for months, enabling analysis of the pathological progression. GBA-/- medaka displayed the pathological phenotypes resembling human neuronopathic GD including infiltration of Gaucher cell-like cells into the brains, progressive neuronal loss, and microgliosis. Detailed pathological findings represented lysosomal abnormalities in neurons and alpha-synuclein (alpha-syn) accumulation in axonal swellings containing autophagosomes. Unexpectedly, disruption of alpha-syn did not improve the life span, formation of axonal swellings, neuronal loss, or neuroinflammation in GBA-/- medaka. Taken together, the present study revealed GBA-/- medaka as a novel neuronopathic GD model, the pahological mechanisms of alpha-syn accumulation caused by GCase deficiency, and the minimal contribution of alpha-syn to the pathogenesis of neuronopathic GD. |
