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

• DOI: 10.1371/journal.pgen.1005065
• Publication Date: 2015-04-03T14:05:53Z
• Authors: Norihito Uemura; Masato Koike; Satoshi Ansai; Masato Kinoshita; Tomoko Ishikawa-F...; Hideaki Matsui; Kiyoshi Naruse; Naoaki Sakamoto; Yasuo Uchiyama; Takeshi Todo; Shunichi Takeda; Hodaka Yamakado; Ryosuke Takahashi
• Keywords: Oryzias; Lysosomal storage disease; Pathogenesis

Homozygous mutations in the glucocerebrosidase (GBA) gene result Gaucher disease (GD), most common lysosomal storage disease. Recent genetic studies have revealed that GBA confer a strong risk for sporadic Parkinson's (PD). To investigate how cause PD, we generated nonsense mutant (GBA-/-) medaka are completely deficient (GCase) activity. In contrast to perinatal death humans and mice lacking GCase activity, GBA-/- survived months, enabling analysis of pathological progression. displayed phenotypes resembling human neuronopathic GD including infiltration cell-like cells into brains, progressive neuronal loss, microgliosis. Detailed findings represented abnormalities neurons alpha-synuclein (α-syn) accumulation axonal swellings containing autophagosomes. Unexpectedly, disruption α-syn did not improve life span, formation swellings, or neuroinflammation medaka. Taken together, present study as novel model, pahological mechanisms caused by deficiency, minimal contribution pathogenesis GD.