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

Thomas M Wishart, Chantal A Mutsaers, Markus Riessland, Michell M Reimer, Gillian Hunter, Marie L Hannam, Samantha L Eaton, Heidi R Fuller, Sarah L Roche, Eilidh Somers, Robert Morse, Philip J Young, Douglas J Lamont, Matthias Hammerschmidt, Anagha Joshi, Peter Hohenstein, Glenn E Morris, Simon H Parson, Paul A Skehel, Thomas BeckerIain M Robinson, Catherina G Becker, Brunhilde Wirth, Thomas H Gillingwater

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

Original languageEnglish
Pages (from-to)1821-1834
Number of pages14
JournalThe Journal of Clinical Investigation
Volume124
Issue number4
Early online date3 Mar 2014
DOIs
Publication statusPublished - Apr 2014

Keywords

  • survival-motor-neuron
  • mouse model
  • SMN protein
  • neuromuscular-junction
  • circuit function
  • defects
  • gene
  • cells
  • drosophila
  • pathology

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