Journal Article Viable Neuronopathic Gaucher Disease Model in Medaka (Oryzias latipes) Displays Axonal Accumulation of Alpha-Synuclein.

Uemura, Norihito  ,  Koike, Masato  ,  Ansai, Satoshi  ,  Kinoshita, Masato  ,  Ishikawa-Fujiwara, Tomoko  ,  Matsui, Hideaki  ,  Naruse, Kiyoshi  ,  Sakamoto, Naoaki  ,  Uchiyama, Yasuo  ,  Todo, Takeshi  ,  Takeda, Shunichi  ,  Yamakado, Hodaka  ,  Takahashi, Ryosuke

11 ( 4 ) 2015-04-02 , Public Library of Science
パーキンソン病の解明に役立つメダカの作製に成功 -メダカが神経変性疾患の研究に貢献できる可能性- 京都大学プレスリリース. 2015-04-09.
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.

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