Objective: This study was performed to determine the pathological role of GBA2 in the central nervous system(CNS) in Gaucher’s disease (GD) and GBA1-related Parkinson’s disease (PD).

Background: 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 is a strong risk factor for sporadic PD. The GBA1 mutations are responsible for 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, also cleaves glucosylceramide to glucose and ceramide. 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 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. GBA2 KO medaka did not show infertilization or apparent abnormal motor phenotypes. All GBA1 / GBA2 double KO medaka showed abnormal swimming at two months. There were no differences in life span or the loss of DA/NA cells between GBA1-/-; GBA2+/+ and GBA1-/-; GBA2-/-. Moreover, the deletion of GBA2 in GBA1 KO medaka didn’t reduce the amount of sphingosine.

Conclusions: Although further analysis is needed, it seems that the deletion of GBA2 in GBA1 KO medaka does not reduce the amount of sphingosine or rescue the pathology of CNS.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/is-the-gba2-a-new-modifier-for-gaucherss-disease-and-gba1-related-parkinsons-disease/