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Dysregulation of ubiquitin homeostasis and ß-catenin signaling promote spinal muscular atrophy

Wishart, TM; Becker, CG; Wirth, B; Gillingwater, TH; Parson, SH; Skehel, PA; Becker, T; Robinson, IM; Mutsaers, CA; Riessland, M; Reimer, MM; Hunter, G; Hannam, ML; Eaton, SL; Fuller, HR; Roche, SL; Somers, E; Morse, R; Young, PJ; Lamont, DJ; Hammerschmidt, M; Joshi, A; Hohenstein, P; Morris, GE

Dysregulation of ubiquitin homeostasis and ß-catenin signaling promote spinal muscular atrophy Thumbnail


Authors

TM Wishart

CG Becker

B Wirth

TH Gillingwater

SH Parson

PA Skehel

T Becker

IM Robinson

CA Mutsaers

M Riessland

MM Reimer

G Hunter

ML Hannam

SL Eaton

SL Roche

E Somers

R Morse

PJ Young

DJ Lamont

M Hammerschmidt

A Joshi

P Hohenstein

GE Morris



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 ß-catenin accumulation, and pharmacological inhibition of ß-catenin robustly ameliorated neuromuscular pathology in zebrafish, Drosophila, and mouse models of SMA. UBA1-associated disruption of ß-catenin was restricted to the neuromuscular system in SMA mice; therefore, pharmacological inhibition of ß-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 ß-catenin signaling, highlighting ubiquitin homeostasis and ß-catenin as potential therapeutic targets for SMA.

Acceptance Date Dec 20, 2013
Publication Date Apr 1, 2014
Publicly Available Date Mar 28, 2024
Journal Journal of Clinical Investigation
Print ISSN 0021-9738
Publisher American Society for Clinical Investigation
Pages 1821 -1834
DOI https://doi.org/10.1172/JCI71318
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
Publisher URL http://dx.doi.org/10.1172/JCI71318