Objective: This experiment was conducted to elucidate the molecular pathogenesis of Parkinson’s disease (PD) and identify potential treatments.

Background: PD is one of the most prevalent neurodegenerative disorders, but there is currently no disease modifying-therapy available. Recent genetic studies have identified heterozygous mutations in the GBA1 gene as a strong risk factor for sporadic PD. Previously, we have reported that the gba1 knock-out (KO) medaka display abnormal swimming movement, non-selective neuronal loss, and α-synuclein accumulation in the brains [1]. We have established a system in which candidate compounds are administered to gba1 KO medaka to examine whether they improve the GBA1-related phenotypes.

Method: The candidate compounds were administered to gba1 KO medaka from the 4 weeks post-fertilization prior to the onset of motor symptoms, and the survival rate was analyzed.

Results: The protein X inhibitor could improve the survival rate. Furthermore, in A53T SNCA bacterial artificial chromosome transgenic mice which serve as a prodromal model of PD [2], the expression level of protein X was increased over time compared to that in wild type mouse.

Conclusion: The gba1 KO medaka are useful to investigate the research on GBA1-related disorder. The protein X may be a key player in the pathophysiology of PD and could represent a novel therapeutic target.

References: [1] Uemura N, et al. Viable neuronopathic Gaucher disease model in Medaka (Oryzias latipes) displays axonal accumulation of alpha-synuclein. PLoS genetics. 2015;11(4):e1005065.
[2]T Taguchi, et al. α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model. Brain. 2020;143(1):249-265.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/protein-x-a-key-player-in-parkinsons-disease-pathophysiology-insights-from-compound-screening-in-gba1-knock-out-medaka/