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.
Highlights
Homozygous mutations in GBA1 are responsible for Gaucher’s disease (GD), the most common lysosomal storage disorder
Perturbation of the sphingolipid metabolism may be one of the causes of the asyn accumulation in the brains of gba2 KO medaka. Because both autophagic-lysosomal pathway (ALP) dysfunction and the perturbation of the sphingolipid metabolism presumably leads to asyn accumulation in gba1 KO medaka [33], we examined the autophagic function in gba2 KO medaka. p62 acts as a linker between microtubule-associated protein 1 light chain 3 (LC3) and poly-ubiquitinated proteins
This study revealed that the deletion of Gba2 in gba1 KO medaka did not rescue the phenotypes, including the altered sphingolipid metabolism and asyn accumulation in the brains
Summary
Homozygous mutations in GBA1 are responsible for Gaucher’s disease (GD), the most common lysosomal storage disorder. Pathological analysis revealed the presence of Lewy bodies in the brains of both GD1 patients and GBA1 heterozygotes with PD (GBA1-PD), suggesting that GBA1 mutations contribute to asyn aggregation [8,9,10,11,12]. The deletion of GBA2 rescues the CNS phenotypes, such as neuronal cell loss, motor coordination and lifespan, in the Niemann-Pick Type C (NPC) mouse model, which shows a decreased GBA1 activity in the brain [31]. These findings raise the possibility that GBA2 works as a novel factor affecting the CNS pathology in GBA1-related disorders, including nGD and PD. The present study provides novel insights into the pathological role of GBA2 in nGD and asyn accumulation in the brains
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