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Cell Rep. 2017 Oct 3;21(1):110-125. doi: 10.1016/j.celrep.2017.09.028.

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

Author information

1
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA; Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
2
Department of Neurobiology, Barrow Neurological Institute, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.
3
Department of Cell Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.
4
Department of Neuroscience, University of Arizona, Tucson, AZ 85721, USA.
5
Department of Anatomy and Cell Biology, University of Kansas School of Medicine, Kansas City, KS 66160, USA.
6
Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA.
7
Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA.
8
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.

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.

KEYWORDS:

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

PMID:
28978466
PMCID:
PMC5679478
DOI:
10.1016/j.celrep.2017.09.028
[Indexed for MEDLINE]
Free PMC Article

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