Wishart, TM and Mutsaers, CA and Riessland, M and Reimer, MM and Hunter, G and Hannam, ML and Eaton, SL and Fuller, HR and Roche, SL and Somers, E and Morse, R and Young, PJ and Lamont, DJ and Hammerschmidt, M and Joshi, A and Hohenstein, P and Morris, GE and Parson, SH and Skehel, PA and Becker, T and Robinson, IM and Becker, CG and Wirth, B and Gillingwater, TH (2014) Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy. Journal of Clinical Investigation, 124 (4). 1821 -1834. ISSN 1558-8238

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Abstract

The autosomal recessive neurodegenerative disease spinal muscular atrophy (SMA) results from low levels of survival motor neuron (SMN) protein; however, it is unclear how reduced SMN promotes SMA development. Here, we determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, we observed widespread perturbations in ubiquitin homeostasis, including reduced levels of ubiquitin-like modifier activating enzyme 1 (UBA1). SMN physically interacted with UBA1 in neurons, and disruption of Uba1 mRNA splicing was observed in the spinal cords of SMA mice exhibiting disease symptoms. Pharmacological or genetic suppression of UBA1 was sufficient to recapitulate an SMA-like neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. Dysregulation of UBA1 and subsequent ubiquitination pathways led to β-catenin accumulation, and pharmacological inhibition of β-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of β-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of β-catenin in these animals failed to prevent systemic pathology in peripheral tissues and organs, indicating fundamental molecular differences between neuromuscular and systemic SMA pathology. Our data indicate that SMA-associated reduction of UBA1 contributes to neuromuscular pathogenesis through disruption of ubiquitin homeostasis and subsequent β-catenin signaling, highlighting ubiquitin homeostasis and β-catenin as potential therapeutic targets for SMA.

Item Type: Article
Additional Information: This is the final published version of the article (version of record). It first appeared online via American Society for Clinical Investigation at http://dx.doi.org/10.1172/JCI71318 - please refer to any applicable terms of use of the publisher. Additional publisher statement. "Users of the online version of the JCI have the right to read, download, copy, distribute, print, search, or link to the full texts of these articles. Use of the online version of the JCI constitutes an agreement to comply with this and the following terms. Any copies, in whole or in part, must include the copyright notice or associated license information. Reproduction of material presented in the journal is governed by the "fair use" limitations of US copyright law (detailed at http://www.loc.gov/copyright/title17/)."
Uncontrolled Keywords: Alternative Splicing, Animals, Disease Models, Animal, Drosophila, Homeostasis, Humans, Isoenzymes, Mice, Knockout, Mutant Strains, Transgenic, Muscle, Skeletal, Muscular Atrophy, Spinal, RNA, Messenger, Rats, Signal Transduction, Spinal Cord, Survival of Motor Neuron 1 Protein, Ubiquitin, Ubiquitin-Activating Enzymes, Zebrafish, beta Catenin
Subjects: R Medicine > R Medicine (General)
Related URLs:
Depositing User: Symplectic
Date Deposited: 26 Jul 2017 15:40
Last Modified: 26 Jul 2017 15:50
URI: http://eprints.keele.ac.uk/id/eprint/3797

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