Impact of Gba2 on Neuronopathic Gaucher's Disease and α-synuclein Accumulation in Medaka (Oryzias Latipes)

Overview

Journal Mol Brain

Publisher Biomed Central

Specialties Molecular Biology
Neurology

Date 2021 May 11

PMID 33971917

Citations 4

Authors

Etsuro Nakanishi

Norihito Uemura

Hisako Akiyama

Masato Kinoshita

Sawamura Masanori

Yosuke Taruno

Hodaka Yamakado

Shu-Ichi Matsuzawa

Shunichi Takeda

Yoshio Hirabayashi

Ryosuke Takahashi

Affiliations

Soon will be listed here.

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.

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