Back to Search
Start Over
Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein.
- Source :
- PLoS Genetics, Vol 11, Iss 4, p e1005065 (2015)
- Publication Year :
- 2015
- Publisher :
- Public Library of Science (PLoS), 2015.
-
Abstract
- 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 (α-syn) accumulation in axonal swellings containing autophagosomes. Unexpectedly, disruption of α-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 α-syn accumulation caused by GCase deficiency, and the minimal contribution of α-syn to the pathogenesis of neuronopathic GD.
Details
- Language :
- English
- ISSN :
- 15537390 and 15537404
- Volume :
- 11
- Issue :
- 4
- Database :
- Directory of Open Access Journals
- Journal :
- PLoS Genetics
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.707126108e9415198b5a43c86b96048
- Document Type :
- article
- Full Text :
- https://doi.org/10.1371/journal.pgen.1005065