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Viable Neuronopathic Gaucher Disease Model in Medaka (Oryzias latipes) Displays Axonal Accumulation of Alpha-Synuclein
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نویسنده
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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.
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منبع
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plos genetics - 2015 - دوره : 11 - شماره : 4
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چکیده
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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. © 2015 uemura et al.
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آدرس
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department of neurology,kyoto university graduate school of medicine,kyoto, Japan, department of cell biology and neuroscience,juntendo university graduate school of medicine,tokyo, Japan, division of applied biosciences,kyoto university graduate school of agriculture,kyoto, Japan, division of applied biosciences,kyoto university graduate school of agriculture,kyoto, Japan, department of radiation biology and medical genetics,osaka university graduate school of medicine,suita, Japan, department of neurology,kyoto university graduate school of medicine,kyoto,japan,department of neuroscience,section of integrative physiology,university of miyazaki,miyazaki, Japan, national institute for basic biology,laboratory of bioresources,okazaki, Japan, department of mathematical and life sciences,hiroshima university graduate school of science,higashi-hiroshima, Japan, department of cell biology and neuroscience,juntendo university graduate school of medicine,tokyo, Japan, department of radiation biology and medical genetics,osaka university graduate school of medicine,suita, Japan, department of radiation genetics,kyoto university graduate school of medicine,kyoto,japan,core research for evolutional science and technology science and technology agency,kawaguchi, Japan, department of neurology,kyoto university graduate school of medicine,kyoto,japan,core research for evolutional science and technology science and technology agency,kawaguchi, Japan, department of neurology,kyoto university graduate school of medicine,kyoto,japan,core research for evolutional science and technology science and technology agency,kawaguchi, Japan
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Authors
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