RRC ID 67504
著者 Nakanishi E, Uemura N, Akiyama H, Kinoshita M, Masanori S, Taruno Y, Yamakado H, Matsuzawa SI, Takeda S, Hirabayashi Y, Takahashi R.
タイトル Impact of Gba2 on neuronopathic Gaucher's disease and α-synuclein accumulation in medaka (Oryzias latipes).
ジャーナル Mol Brain
Abstract Homozygous mutations in the lysosomal glucocerebrosidase gene, GBA1, cause Gaucher's disease (GD), while heterozygous mutations in GBA1 are a strong risk factor for Parkinson's disease (PD), whose pathological hallmark is intraneuronal α-synuclein (asyn) aggregates. We previously reported that gba1 knockout (KO) medaka exhibited glucosylceramide accumulation and neuronopathic GD phenotypes, including short lifespan, the dopaminergic and noradrenergic neuronal cell loss, microglial activation, and swimming abnormality, with asyn accumulation in the brains. A recent study reported that deletion of GBA2, non-lysosomal glucocerebrosidase, in a non-neuronopathic GD mouse model rescued its phenotypes. In the present study, we generated gba2 KO medaka and examined the effect of Gba2 deletion on the phenotypes of gba1 KO medaka. The Gba2 deletion in gba1 KO medaka resulted in the exacerbation of glucosylceramide accumulation and no improvement in neuronopathic GD pathological changes, asyn accumulation, or swimming abnormalities. Meanwhile, though gba2 KO medaka did not show any apparent phenotypes, biochemical analysis revealed asyn accumulation in the brains. gba2 KO medaka showed a trend towards an increase in sphingolipids in the brains, which is one of the possible causes of asyn accumulation. In conclusion, this study demonstrated that the deletion of Gba2 does not rescue the pathological changes or behavioral abnormalities of gba1 KO medaka, and GBA2 represents a novel factor affecting asyn accumulation in the brains.
巻・号 14(1)
ページ 80
公開日 2021-5-10
DOI 10.1186/s13041-021-00790-x
PII 10.1186/s13041-021-00790-x
PMID 33971917
PMC PMC8111776
MeSH Alkaline Phosphatase / metabolism Animals Autophagy Brain / enzymology* Brain / pathology* Gaucher Disease / enzymology* Gaucher Disease / pathology Gene Deletion Gene Knockout Techniques Glucosylceramidase / metabolism* Models, Biological Mutation / genetics Neurons / enzymology* Neurons / pathology* Oryzias / metabolism* Phenotype Sphingolipids / metabolism alpha-Synuclein / metabolism*
IF 4.686
リソース情報
ヒト・動物細胞 293T(RCB2202)