title: Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein.
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.
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Uemura
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Division of Applied Biosciences, Kyoto University Graduate School of Agriculture, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ansai
authors.affiliation: Division of Applied Biosciences, Kyoto University Graduate School of Agriculture, Kyoto, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Kinoshita
authors.affiliation: Department of Radiation Biology and Medical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Ishikawa-Fujiwara
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Matsui
authors.affiliation: National Institute for Basic Biology, Laboratory of Bioresources, Okazaki, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Naruse
authors.affiliation: Department of Mathematical and Life Sciences, Hiroshima University Graduate School of Science, Higashi-Hiroshima, Japan.
authors.forename: Naoaki
authors.initials: N
authors.lastname: Sakamoto
authors.affiliation: Department of Cell Biology and Neuroscience, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Uchiyama
authors.affiliation: Department of Radiation Biology and Medical Genetics, Osaka University Graduate School of Medicine, Suita, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Todo
authors.affiliation: Department of Radiation Genetics, Kyoto University Graduate School of Medicine, Kyoto, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Shunichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Hodaka
authors.initials: H
authors.lastname: Yamakado
authors.affiliation: Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, Japan; Core Research for Evolutional Science and Technology, Japan Science and Technology Agency, Kawaguchi, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005776:Gaucher Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005962:Glucosylceramidase / Q000172:deficiency* / Q000235:genetics; D009990:Oryzias / Q000235:genetics* / Q000378:metabolism; D010588:Phagosomes / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase
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