Dysregulation of ubiquitin homeostasis and [Beta]-catenin signaling promote spinal muscular atrophy

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, the authors determined that ubiquitin-dependent pathways regulate neuromuscular patho...

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Bibliographic Details
Published in:The Journal of clinical investigation 2014-04, Vol.124 (4), p.1821
Main Authors: Wishart, Thomas M, Mutsaers, Chantal A, Riessland, Markus, Reimer, Michell M, Hunter, Gillian, Hannam, Marie L, Eaton, Samantha L, Fuller, Heidi R, Roche, Sarah L, Somers, Eilidh, Morse, Robert, Young, Philip J, Lamont, Douglas J, Hammerschmidt, Matthias, Joshi, Anagha, Hohenstein, Peter, Morris, Glenn E, Parson, Simon H, Skehel, Paul A, Becker, Thomas, Robinson, Iain M, Becker, Catherina G, Wirth, Brunhilde, Gillingwater, Thomas H
Format: Article
Language:English
Subjects:
Biomedical research
Disease
Embryos
Homeostasis
Insects
Mortality
Muscular dystrophy
Musculoskeletal system
Mutation
Neurons
Pathogenesis
Pathology
Proteins
Proteomics
Rodents
Studies
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Summary: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, the authors determined that ubiquitin-dependent pathways regulate neuromuscular pathology in SMA. Using mouse models of SMA, they observed widespread perturbations in an 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 SMAlike neuromuscular pathology in zebrafish, suggesting that UBA1 directly contributes to disease pathogenesis. The 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.
ISSN:0021-9738
1558-8238