Neurodegeneration Treatment Team, Centre for Motor Neuron Disease Research, Faculty of Medicine, Health and Human Sciences, Macquarie Medical School, Macquarie University, Sydney 2109, Australia.
Cells. 2021 Sep 29;10(10):2592. doi: 10.3390/cells10102592.
Spinocerebellar ataxia type 3 (SCA3) is a hereditary ataxia caused by inheritance of a mutated form of the human gene containing an expanded CAG repeat region, encoding a human ataxin-3 protein with a long polyglutamine (polyQ) repeat region. Previous studies have demonstrated that ataxin-3 containing a long polyQ length is highly aggregation prone. Cleavage of the ataxin-3 protein by calpain proteases has been demonstrated to be enhanced in SCA3 models, leading to an increase in the aggregation propensity of the protein. Here, we tested the therapeutic potential of a novel calpain inhibitor BLD-2736 for the treatment of SCA3 by testing its efficacy on a transgenic zebrafish model of SCA3. We found that treatment with BLD-2736 from 1 to 6 days post-fertilisation (dpf) improves the swimming of SCA3 zebrafish larvae and decreases the presence of insoluble protein aggregates. Furthermore, delaying the commencement of treatment with BLD-2736, until a timepoint when protein aggregates were already known to be present in the zebrafish larvae, was still successful at removing enhanced green fluorescent protein (EGFP) fused-ataxin-3 aggregates and improving the zebrafish swimming. Finally, we demonstrate that treatment with BLD-2736 increased the synthesis of LC3II, increasing the activity of the autophagy protein quality control pathway. Together, these findings suggest that BLD-2736 warrants further investigation as a treatment for SCA3 and related neurodegenerative diseases.
脊髓小脑性共济失调 3 型（SCA3）是一种遗传性共济失调，由携带突变人类基因的遗传引起，该基因包含扩展的 CAG 重复区域，编码具有长多聚谷氨酰胺（polyQ）重复区域的人类共济失调蛋白-3。先前的研究表明，含有长 polyQ 长度的共济失调蛋白-3极易聚集。已经证明，钙蛋白酶蛋白酶对 SCA3 模型中的共济失调蛋白-3的切割被增强，导致蛋白质聚集倾向增加。在这里，我们通过测试 SCA3 转基因斑马鱼模型来测试新型钙蛋白酶抑制剂 BLD-2736 治疗 SCA3 的治疗潜力。我们发现，从受精后 1 至 6 天（dpf）开始用 BLD-2736 治疗可改善 SCA3 斑马鱼幼虫的游泳能力，并减少不溶性蛋白聚集体的存在。此外，延迟 BLD-2736 治疗的开始时间，直到已经知道蛋白聚集体存在于斑马鱼幼虫中，仍然可以成功去除融合增强型绿色荧光蛋白（EGFP）的共济失调蛋白-3聚集体并改善斑马鱼的游泳能力。最后，我们证明用 BLD-2736 治疗可增加 LC3II 的合成，从而增加自噬蛋白质量控制途径的活性。总之，这些发现表明 BLD-2736 值得进一步研究，作为治疗 SCA3 和相关神经退行性疾病的方法。
