Electrical silencing of dendritic arborization neurons rescues toxic polyglutamine-induced locomotion defect

This study investigates the effects of polyglutamine (polyQ) expansions on the locomotion of <i>Drosophila</i> larvae, focusing on the role of class IV dendritic arborization (da) neurons. PolyQ expansions are associated with neurodegenerative diseases like Huntington’s disease, and <i>Drosophila</i> is a valuable model organism for studying these diseases due to its genetic tractability and short generation time. We found that expressing a polyQ protein in class IV da neurons caused significant locomotion deficits. Specifically, larvae with polyQ expression exhibited slower crawling speed and increased turn frequency, indicating impaired movement. The most intriguing finding of our study was that electrically silencing class IV da neurons completely rescued the locomotion deficits caused by polyQ expression. By expressing a potassium channel that makes the neurons less active, we effectively reversed the locomotion defects. This suggests that modulating the activity of these neurons could be a promising therapeutic approach for treating polyQ diseases. Our findings have significant implications for understanding polyQ diseases and developing new therapeutic approaches. By electrically silencing these neurons, we may be preventing the harmful effects of polyQ-induced cation channels, which are thought to disrupt cellular function. This opens up exciting possibilities for exploring electrical silencing as a potential treatment for polyQ diseases, offering hope for future therapies that target the underlying mechanisms of these devastating conditions.

本研究探讨了多聚谷氨酰胺（polyQ）扩增对果蝇（Drosophila）幼虫运动行为的影响，重点关注第四类树突分枝神经元（dendritic arborization, da）的作用。多聚谷氨酰胺扩增与亨廷顿病等神经退行性疾病密切相关，而果蝇因其遗传可操作性强、世代周期短，成为研究此类疾病的优质模式生物。我们发现，在第四类树突分枝神经元中表达多聚谷氨酰胺蛋白会引发显著的运动功能缺陷。具体而言，表达多聚谷氨酰胺的幼虫爬行速度减慢、转向频率升高，表明其运动能力受损。本研究最引人关注的发现是，对第四类树突分枝神经元进行电沉默可完全逆转多聚谷氨酰胺蛋白表达引发的运动缺陷。通过表达一种可降低神经元活性的钾通道，我们有效改善了运动障碍。这提示，调控此类神经元的活性或可成为治疗多聚谷氨酰胺疾病的潜在有效策略。本研究结果对于解析多聚谷氨酰胺疾病的发病机制、开发新型治疗手段具有重要意义。通过电沉默此类神经元，我们或可阻断多聚谷氨酰胺诱导的阳离子通道所介导的有害效应——此类通道被认为会破坏细胞正常功能。这为探索电沉默作为多聚谷氨酰胺疾病的潜在治疗方案开辟了全新方向，为靶向此类毁灭性疾病核心发病机制的未来疗法带来了希望。