Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA; Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
Cell Rep. 2017 Oct 3;21(1):110-125. doi: 10.1016/j.celrep.2017.09.028.
Amyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to ∼97% of ALS cases. Using a Drosophila model of ALS, we show that TDP-43 overexpression (OE) in motor neurons results in decreased expression of the Hsc70-4 chaperone at the neuromuscular junction (NMJ). Mechanistically, mutant TDP-43 sequesters hsc70-4 mRNA and impairs its translation. Expression of the Hsc70-4 ortholog, HSPA8, is also reduced in primary motor neurons and NMJs of mice expressing mutant TDP-43. Electrophysiology, imaging, and genetic interaction experiments reveal TDP-43-dependent defects in synaptic vesicle endocytosis. These deficits can be partially restored by OE of Hsc70-4, cysteine-string protein (Csp), or dynamin. This suggests that TDP-43 toxicity results in part from impaired activity of the synaptic CSP/Hsc70 chaperone complex impacting dynamin function. Finally, Hsc70-4/HSPA8 expression is also post-transcriptionally reduced in fly and human induced pluripotent stem cell (iPSC) C9orf72 models, suggesting a common disease pathomechanism.
肌萎缩侧索硬化症（ALS）是一种突触病，伴有包含 TDP-43 的细胞质聚集物的存在，TDP-43 是一种与大约 97%的 ALS 病例相关的 RNA 结合蛋白。使用 ALS 的果蝇模型，我们表明运动神经元中 TDP-43 的过表达（OE）导致神经肌肉接点（NMJ）中 Hsc70-4 伴侣的表达减少。从机制上讲，突变 TDP-43 隔离 hsc70-4 mRNA 并损害其翻译。表达 Hsc70-4 的同源物 HSPA8 在表达突变 TDP-43 的原代运动神经元和 NMJ 中也减少。电生理学、成像和遗传相互作用实验揭示了 TDP-43 依赖性突触囊泡内吞作用缺陷。这些缺陷可以部分通过 Hsc70-4、半胱氨酸-string 蛋白（Csp）或 dynamin 的 OE 来恢复。这表明 TDP-43 的毒性部分是由于突触 CSP/Hsc70 伴侣复合物的活性受损，影响 dynamin 的功能。最后，在果蝇和人类诱导多能干细胞（iPSC）C9orf72 模型中，Hsc70-4/HSPA8 的表达也在转录后减少，这表明存在共同的疾病发病机制。
