Objective: This study was performed to explore the therapeutic target for Lewy body disease.

Background: Lewy body disease (LBD), including Parkinson’s disease and diffuse Lewy body disease, is one of the most prevalent neurodegenerative disorders, yet effective disease-modifying therapies are still lacking. Recent genetic studies have identified heterozygous mutations in the GBA1 gene as a strong risk factor for LBD. We have previously demonstrated that gba1 knock-out (KO) medaka exhibit abnormal swimming movements, non-selective neuronal cell loss, and α-synuclein accumulation in the brain. Additionally, we have also established a system in which candidate compounds are administered to gba1 KO medaka to assess their potential to ameliorate phenotypes of gba1 KO medaka.

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

Results: The necroptosis inhibitor significantly improved the survival rate. Furthermore, the expression level of mixed lineage kinase domain-like protein (MLKL), a key mediator of necroptosis, was elevated in the LBD mice model (A53T SNCA bacterial artificial chromosome transgenic mice) and aged mice compared to wild-type or young mice.

Conclusion: This drug administration system in medaka has proven useful in exploring potential therapeutic candidates. Necroptosis emerges as a promising therapeutic target for LBD.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/exploring-the-therapeutic-target-for-lewy-body-disease-using-gba1-knock-out-medaka/