Disruption in the autophagic process underlies the sensory neuropathy in <i>dystonia musculorum</i> mice

A homozygous mutation in the <i>DST</i> (dystonin) gene causes a newly identified lethal form of hereditary sensory and autonomic neuropathy in humans (HSAN-VI). DST loss of function similarly leads to sensory neuron degeneration and severe ataxia in <i>dystonia musculorum</i> (<i>Dst</i>^<i>dt</i>) mice. DST is involved in maintaining cytoskeletal integrity and intracellular transport. As autophagy is highly reliant upon stable microtubules and motor proteins, we assessed the influence of DST loss of function on autophagy using the <i>Dst</i>^{<i>dt-Tg4</i>} mouse model. Electron microscopy (EM) revealed an accumulation of autophagosomes in sensory neurons from these mice. Furthermore, we demonstrated that the autophagic flux was impaired. Levels of LC3-II, a marker of autophagosomes, were elevated. Consequently, <i>Dst</i>^{<i>dt-Tg4</i>} sensory neurons displayed impaired protein turnover of autophagosome substrate SQTSM1/p62 and of polyubiquitinated proteins. Interestingly, in a previously described <i>Dst</i>^{<i>dt-Tg4</i>} mouse model that is partially rescued by neuronal specific expression of the DST-A2 isoform, autophagosomes, autolysosomes, and damaged organelles were reduced when compared to <i>Dst</i>^{<i>dt-Tg4</i>} mutant mice. LC3-II, SQTSM1, polyubiquitinated proteins and autophagic flux were also restored to wild-type levels in the rescued mice. Finally, a significant decrease in DNAIC1 (dynein, axonemal, intermediate chain 1; the mouse ortholog of human DNAI1), a member of the DMC (dynein/dynactin motor complex), was noted in <i>Dst</i>^{<i>dt-Tg4</i>} dorsal root ganglia and sensory neurons. Thus, DST-A2 loss of function perturbs late stages of autophagy, and dysfunctional autophagy at least partially underlies <i>Dst</i>^<i>dt</i> pathogenesis. We therefore conclude that the DST-A2 isoform normally facilitates autophagy within sensory neurons to maintain cellular homeostasis.<i>DST</i>基因（dystonin）的纯合突变可引发人类一种新鉴定的致死性遗传性感觉自主神经病6型（HSAN-VI）。<i>Dst</i>功能缺失同样可导致<i>dystonia musculorum</i>（<i>Dst</i>^<i>dt</i>）小鼠出现感觉神经元变性与严重共济失调。DST参与维持细胞骨架完整性与细胞内物质运输。由于自噬（autophagy）高度依赖稳定的微管与动力蛋白，我们借助<i>Dst</i>^{<i>dt-Tg4</i>}小鼠模型评估了DST功能缺失对自噬的影响。电子显微镜（electron microscopy, EM）观察显示，该模型小鼠感觉神经元内出现自噬体蓄积。此外，我们证实自噬流受到损伤，自噬体标志物LC3-II的水平显著升高。因此，<i>Dst</i>^{<i>dt-Tg4</i>}小鼠的感觉神经元中，自噬体底物SQSTM1/p62以及多泛素化蛋白的蛋白质周转均受损。值得注意的是，在先前报道的可通过神经元特异性表达DST-A2亚型实现部分表型挽救的<i>Dst</i>^{<i>dt-Tg4</i>}小鼠模型中，与未挽救的<i>Dst</i>^{<i>dt-Tg4</i>}突变小鼠相比，其自噬体、自噬溶酶体以及受损细胞器的蓄积量均有所减少。挽救小鼠体内的LC3-II、SQSTM1、多泛素化蛋白水平以及自噬流均恢复至野生型小鼠水平。最后，在<i>Dst</i>^{<i>dt-Tg4</i>}小鼠的背根神经节与感觉神经元中，DMC（动力蛋白/动力激活蛋白复合物，dynein/dynactin motor complex）成员DNAIC1（动力蛋白轴丝中间链1，人类DNAI1的小鼠同源物）的水平显著降低。综上，DST-A2功能缺失会干扰自噬的晚期阶段，而自噬功能障碍至少部分参与了<i>Dst</i>^<i>dt</i>小鼠的发病机制。因此我们认为，DST-A2亚型通常可在感觉神经元中促进自噬过程，以维持细胞稳态。

搜集汇总

背景与挑战

背景概述

该数据集基于一项研究，探讨了DST基因突变导致的自噬过程破坏如何引发dystonia musculorum小鼠的感觉神经病变。研究使用Dst dt-Tg4小鼠模型，通过实验发现自噬体积累、自噬通量受损以及相关蛋白水平异常，并表明DST-A2亚型表达可部分恢复自噬功能，从而维持神经元稳态。数据集涵盖了实验数据、分析结果和学科交叉信息，适用于神经科学和细胞生物学领域的研究。