Abstract：
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder caused by mutant ataxin-3 with an abnormally expanded polyQ tract and is the most common dominantly inherited ataxia worldwide. There are no suitable therapeutic options for this disease. Autophagy, a defense mechanism against the toxic effects of aggregation-prone misfolded proteins, has been shown to have beneficial effects on neurodegenerative diseases. Thus, trehalose, which is an autophagy inducer, may have beneficial effects on SCA3. In the present study, we examined the effects of trehalose on an SCA3 cell model. After trehalose treatment, aggregate formation, soluble ataxin-3 protein levels and cell viability were evaluated in HEK293T cells overexpressing ataxin-3-15Q or ataxin-3-77Q. We also explored the mechanism by which trehalose affects autophagy and stress pathways. A filter trap assay showed that trehalose decreased the number of aggregates formed by mutant ataxin-3 containing an expanded polyQ tract. Western blot and Cell Counting Kit-8 (CCK-8) results demonstrated that trehalose also reduced the ataxin-3 protein levels and was safe for ataxin-3-expressing cells, respectively. Western blot and total antioxidant capacity assays suggested that trehalose had great therapeutic potential for treating SCA3, likely through its antioxidant activity. Our data indicate that trehalose plays a neuroprotective role in SCA3 by inhibiting the aggregation and reducing the protein level of ataxin-3, which is also known to protect against oxidative stress. These findings provide a new insight into the possibility of treating SCA3 with trehalose and highlight the importance of inducing autophagy in SCA3.
摘要：
脊髓小脑共济失调3型（SCA3）是由突变型共济失调蛋白3引起的神经退行性疾病，具有异常扩张的polyQ束，是全球最常见的显性遗传性共济失调。对于这种疾病没有合适的治疗选择。自噬,针对易于聚集的错误折叠蛋白质的毒性作用的防御机制，已被证明对神经退行性疾病有有益的作用。因此，海藻糖,这是一种自噬诱导剂，可能对SCA3有有益的影响。在本研究中,我们研究了海藻糖对SCA3细胞模型的影响。海藻糖治疗后，聚集体形成,在过表达ataxin-3-15Q或ataxin-3-77Q的HEK293T细胞中评估可溶性ataxin-3蛋白水平和细胞活力。我们还探讨了海藻糖影响自噬和应激途径的机制。过滤陷阱分析显示，海藻糖减少了包含扩展的polyQ束的突变ataxin-3形成的聚集体的数量。蛋白质印迹和细胞计数试剂盒-8（CCK-8）结果表明，海藻糖也降低了ataxin-3蛋白水平，并且对表达ataxin-3的细胞是安全的，分别。Westernblot和总抗氧化能力测定表明，海藻糖可能通过其抗氧化活性具有治疗SCA3的巨大治疗潜力。我们的数据表明，海藻糖通过抑制聚集和降低ataxin-3的蛋白质水平在SCA3中发挥神经保护作用，ataxin-3也被认为可以防止氧化应激。这些发现为海藻糖治疗SCA3的可能性提供了新的见解，并强调了在SCA3中诱导自噬的重要性。
