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dc.contributor.authorCoyne, Alyssa N.
dc.contributor.authorLorenzini, Ileana
dc.contributor.authorChou, Ching-Chieh
dc.contributor.authorTorvund, Meaghan
dc.contributor.authorRogers, Robert S.
dc.contributor.authorStarr, Alexander
dc.contributor.authorZaepfel, Benjamin L.
dc.contributor.authorLevy, Jennifer
dc.contributor.authorJohannesmeyer, Jeffrey
dc.contributor.authorSchwartz, Jacob C.
dc.contributor.authorNishimune, Hiroshi
dc.contributor.authorZinsmaier, Konrad
dc.contributor.authorRossoll, Wilfried
dc.contributor.authorSattler, Rita
dc.contributor.authorZarnescu, Daniela C.
dc.date.accessioned2017-11-06T16:36:04Z
dc.date.available2017-11-06T16:36:04Z
dc.date.issued2017-10
dc.identifier.citationPost-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALS 2017, 21 (1):110 Cell Reportsen
dc.identifier.issn22111247
dc.identifier.pmid28978466
dc.identifier.doi10.1016/j.celrep.2017.09.028
dc.identifier.urihttp://hdl.handle.net/10150/625980
dc.description.abstractAmyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to similar 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.
dc.description.sponsorshipNIH K-INBRE postdoctoral award [P20 GM103418]; NIH [R00 NS082376, R01NS078214, R01AG051470, R21 NS094809, RO1 NS091299]; Emory Medicine Catalyst Award; Muscular Dystrophy Association [MDA348086]; ALS Association ALSA [16-IIP-278]; Barrow Neurological Foundation; Himelic Family Foundation; Neuroscience Graduate Interdisciplinary Program at UA; ARCSen
dc.language.isoenen
dc.publisherCELL PRESSen
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S2211124717313037en
dc.rights© 2017 The Author(s). This is an open access article under the CC BY-NC-ND license.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/
dc.titlePost-transcriptional Inhibition of Hsc70-4/HSPA8 Expression Leads to Synaptic Vesicle Cycling Defects in Multiple Models of ALSen
dc.typeArticleen
dc.contributor.departmentUniv Arizona, Dept Mol & Cellular Biolen
dc.contributor.departmentUniv Arizona, Dept Neuroscien
dc.contributor.departmentUniv Arizona, Dept Neurolen
dc.contributor.departmentUniv Arizona, Dept Chem & Biochemen
dc.identifier.journalCell Reportsen
dc.description.collectioninformationThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.en
dc.eprint.versionFinal published versionen
refterms.dateFOA2018-09-11T23:55:32Z
html.description.abstractAmyotrophic lateral sclerosis (ALS) is a synaptopathy accompanied by the presence of cytoplasmic aggregates containing TDP-43, an RNA-binding protein linked to similar 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.


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© 2017 The Author(s). This is an open access article under the CC BY-NC-ND license.
Except where otherwise noted, this item's license is described as © 2017 The Author(s). This is an open access article under the CC BY-NC-ND license.