Impact of Gba2 on neuronopathic Gaucher’s disease and α-synuclein accumulation in medaka (Oryzias latipes)

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.

Impact of GBA2 on Neuronopathic Gaucher’s Disease and α-Synuclein Accumulation in Medaka (Oryzias Latipes)

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, non-selective neuron 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.

Biomarkers of Parkinson’s disease in carriers of mutations in the glucocerebrosidase gene

Оценка гексозилсфингозина (HexSph), в крови в настоящее время является чувствительным диагностическим тестом развития болезни Гоше. Мы предположили, что оценка данного метаболита может быть эффективна при выявлении развития болезни Паркинсона (БП) у носителей мутаций в гене GBA (GBA-БП). Концентрация HexSph и ферментативная активность GBA была оценена у пациентов с GBA-БП, бессимптомных носителей мутации в гене GBA, пациентов со спорадической БП (сБП) и в контрольной группе в крови, а также в первичной культуре культивируемых макрофагов. Показано, что оценка уровня HexSph в первичной культуре макрофагов позволяет отличить заболевших БП носителей мутаций в гене GBA, от бессимптомных носителей мутаций и может быть рассмотрена как биомаркер развития БП у носителей мутаций в гене GBA. Assessment of hexosylsphingosine (HexSph) in the blood is currently a sensitive diagnostic test for Gaucher disease. We suggested that the assessment of this metabolite may be effective in detecting the development of Parkinson’s disease (PD) in mutation carriers in the GBA gene (GBA-PD). In the present study HexSph concentration and GBA enzymatic activity were evaluated in patients with GBA-BP, asymptomatic carriers of GBA mutations, patients with sporadic PD (sPD) and the control group in blood, as well as in the primary culture of macrophages. An assessment of HexSph level in the primary macrophage culture makes it possible to distinguish GBA mutation carriers with PD from asymptomatic mutation carriers, and though could be considered as a biomarker of PD development in carriers of GBA mutations.