Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS

Alyssa N. Coyne, Ileana Lorenzini, Ching Chieh Chou, Meaghan Torvund, Robert S. Rogers, Alexander Starr, Benjamin L. Zaepfel, Jennifer Levy, Jeffrey Johannesmeyer, Jacob C. Schwartz, Hiroshi Nishimune, Konrad Zinsmaier, Wilfried Rossoll, Rita Sattler, Daniela C. Zarnescu

Research output: Contribution to journalArticle

25 Scopus citations

Abstract

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. 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.

Original languageEnglish (US)
Pages (from-to)110-125
Number of pages16
JournalCell Reports
Volume21
Issue number1
DOIs
StatePublished - Oct 3 2017

Keywords

  • C9orf72
  • Drosophila
  • RNA processing
  • TDP-43
  • amyotrophic lateral sclerosis
  • endocytosis
  • iPSC
  • neuromuscular junction
  • synaptic vesicle cycle
  • translation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Coyne, A. N., Lorenzini, I., Chou, C. C., Torvund, M., Rogers, R. S., Starr, A., Zaepfel, B. L., Levy, J., Johannesmeyer, J., Schwartz, J. C., Nishimune, H., Zinsmaier, K., Rossoll, W., Sattler, R., & Zarnescu, D. C. (2017). Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS. Cell Reports, 21(1), 110-125. https://doi.org/10.1016/j.celrep.2017.09.028