期刊
PLOS GENETICS
卷 11, 期 4, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pgen.1005065
关键词
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资金
- Ministry of Education, Culture, Sports, Science and Technology of Japan [23111001]
- Grants-in-Aid for Scientific Research [26860666, 25460276, 221S0003, 26111519, 13J01682, 15K19486, 15H02540] Funding Source: KAKEN
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.
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