Objective: This study was performed to determine the pathological role of GBA2 in the CNS in GD and GBA1-related PD.

Background: Parkinson’s disease (PD) is one of the most prevalent neurodegenerative disorders characterized by tremor, rigidity, akinesia and postural instability. Recent genetic studies have identified that heterozygous mutations in the GBA1 gene are a strong risk factor for sporadic PD. Homozygous mutations in GBA1 gene are responsible for Gaucher’s disease (GD), the common autosomal recessive lysosomal storage disease. We have reported that the GBA1 knock-out (KO) medaka can survive long enough for pathological analysis of disease progression in contrast to the perinatal death of GBA1 KO mice. These GBA1 KO medaka display abnormal swimming movement, non-selective neuronal loss, and α-synuclein accumulation in the brains. These GBA1 KO medaka are useful to investigate the mechanisms of α-synuclein accumulation in GD and GBA1-related PD. The non-lysosomal β-Glucosidase (GBA2), which is localized at the endoplasmic reticulum and Golgi apparatus, cleaves glucosylceramide to glucose and ceramide like GBA1. A recent study has reported that the deletion of GBA2 rescues the visceral manifestations in type1 GD mice model through reduction of sphingosine. To date, it remains unclear whether the deletion of GBA2 can modify the central nervous system (CNS) manifestations of GD.

Methods: We generated GBA2 KO medaka by clustered regularly interspaced short palindromic repeat (CRISPR) / CRISPR-associated nuclease (Cas9) system. Then, we crossed GBA2 KO medaka with GBA1 KO medaka to examine the genetic interaction between GBA1 and GBA2 in GD and GBA1-related PD.

Results: We have successfully generated GBA2 KO medaka by CRISPR / Cas9. GBA2 KO medaka lack both GBA2 enzymatic activity and protein expression. There were no differences in life span or the loss of dopaminergic cells between GBA1-/-; GBA2+/+ and GBA1-/-; GBA2-/-. Moreover, the deletion of GBA2 in GBA1 KO medaka didn’t reduce the amount of sphingosine, the presumptive culprit in the pathophysiology of GD, and increased the amount of α-synuclein in the brains.

Conclusions: The deletion of GBA2 in GBA1 KO medaka didn’t reduce the amount of sphingosine or rescue the pathology of CNS. Moreover, the accumulation of α-synuclein was exacerbated by the deletion of GBA2 in GBA1 KO medaka.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/deletion-of-gba2-in-neuronopathic-gauchers-disease-medaka-cant-rescue-the-phenotype/