Department of Neurology, Kyoto University Graduate School of Medicine, Kyoto, 606-8507, Japan.
Department of Pathology and Laboratory Medicine, Institute On Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, 19104-2676, USA.
Mol Brain. 2021 May 10;14(1):80. doi: 10.1186/s13041-021-00790-x.
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.
溶酶体葡萄糖脑苷脂酶基因 GBA1 的纯合突变导致戈谢病（GD），而 GBA1 的杂合突变是帕金森病（PD）的一个强烈危险因素，其病理特征是神经元内α-突触核蛋白（asyn）聚集。我们之前报道过 gba1 敲除（KO）斑马鱼表现出葡萄糖脑苷脂积累和神经病变 GD 表型，包括寿命缩短、多巴胺能和去甲肾上腺素能神经元细胞丢失、小胶质细胞激活和游泳异常，同时大脑中 asyn 积累。最近的一项研究报道，非溶酶体葡萄糖脑苷脂酶 GBA2 的缺失在非神经病变 GD 小鼠模型中挽救了其表型。在本研究中，我们生成了 gba2 KO 斑马鱼，并研究了 Gba2 缺失对 gba1 KO 斑马鱼表型的影响。gba1 KO 斑马鱼中 Gba2 的缺失导致葡萄糖脑苷脂积累加剧，而对神经病变 GD 病理变化、asyn 积累或游泳异常没有改善。同时，尽管 gba2 KO 斑马鱼没有表现出任何明显的表型，但生化分析显示大脑中 asyn 积累。gba2 KO 斑马鱼大脑中的神经鞘脂略有增加，这可能是 asyn 积累的原因之一。总之，本研究表明 Gba2 的缺失不能挽救 gba1 KO 斑马鱼的病理变化或行为异常，GBA2 是影响大脑中 asyn 积累的一个新因素。
