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

Authors :
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
Source :
Cell Reports, Vol 21, Iss 1, Pp 110-125 (2017)
Publication Year :
2017
Publisher :
Elsevier, 2017.

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.

Details

Language :
English
ISSN :
22111247
Volume :
21
Issue :
1
Database :
Directory of Open Access Journals
Journal :
Cell Reports
Publication Type :
Academic Journal
Accession number :
edsdoj.864d5b20cac14a2c8ea1e98ca71ebe07
Document Type :
article
Full Text :
https://doi.org/10.1016/j.celrep.2017.09.028