Amyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to âˆ¼97% 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. Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by synaptic failure. Coyne et al. show that in multiple models of ALS, ranging from Drosophila to mice to patient-derived motor neurons, deficits in synaptic vesicle cycling can be explained by dysregulation of the Hsc70-4/HSPA8 chaperone.
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Coyne, Alyssa N.; Lorenzini, Ileana; Chou, Ching Chieh; Torvund, Meaghan; Rogers, Robert S.; Starr, Alexander; Zaepfel, Benjamin L.; Levy, Jennifer; Johannesmeyer, Jeffrey; Schwartz, Jacob C.; Nishimune, Hiroshi; Zinsmaier, Konrad; Rossoll, Wilfried; Sattler, Rita; and Zarnescu, Daniela C., "Post-Transcriptional Inhibition Of Hsc70-4/Hspa8 Expression Leads To Synaptic Vesicle Cycling Defects In Multiple Models Of Als" (2017). Neurobiology. 368.