Post-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS.
Autor: | Coyne AN; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA; Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA., Lorenzini I; Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA., Chou CC; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA., Torvund M; Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA., Rogers RS; Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 66160, USA., Starr A; Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA., Zaepfel BL; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA., Levy J; Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA., Johannesmeyer J; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA., Schwartz JC; Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA., Nishimune H; Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 66160, USA., Zinsmaier K; Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA; Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA., Rossoll W; Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA., Sattler R; Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA., Zarnescu DC; 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 Neurology, University of Arizona, Tucson, AZ 85721, USA. Electronic address: zarnescu@email.arizona.edu. |
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Jazyk: | angličtina |
Zdroj: | Cell reports [Cell Rep] 2017 Oct 03; Vol. 21 (1), pp. 110-125. |
DOI: | 10.1016/j.celrep.2017.09.028 |
Abstrakt: | 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. (Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.) |
Databáze: | MEDLINE |
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