RRC ID 33327
著者 Uemura N, Koike M, Ansai S, Kinoshita M, Ishikawa-Fujiwara T, Matsui H, Naruse K, Sakamoto N, Uchiyama Y, Todo T, Takeda S, Yamakado H, Takahashi R.
タイトル Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein.
ジャーナル PLoS Genet
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.
巻・号 11(4)
ページ e1005065
公開日 2015-4-1
DOI 10.1371/journal.pgen.1005065
PII PGENETICS-D-14-03033
PMID 25835295
PMC PMC4383526
MeSH Animals Axons / metabolism* Axons / ultrastructure Disease Models, Animal Gaucher Disease / genetics* Gaucher Disease / metabolism Gaucher Disease / pathology Glucosylceramidase / deficiency* Glucosylceramidase / genetics Oryzias / genetics* Oryzias / metabolism Phagosomes / metabolism alpha-Synuclein / metabolism*
IF 5.175
引用数 32
WOS 分野 GENETICS & HEREDITY
リソース情報
メダカ TILLING_MUTANT Kyoto-Cab (OK-Cab(MT830))