Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy
Thomas M. Wishart, … , Brunhilde Wirth, Thomas H. Gillingwater
Thomas M. Wishart, … , Brunhilde Wirth, Thomas H. Gillingwater
Published March 3, 2014
Citation Information: J Clin Invest. 2014;124(4):1821-1834. https://doi.org/10.1172/JCI71318.
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Dysregulation of ubiquitin homeostasis and β-catenin signaling promote spinal muscular atrophy

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.

Authors

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 Becker, Iain M. Robinson, Catherina G. Becker, Brunhilde Wirth, Thomas H. Gillingwater

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Figure 7

Pharmacological inhibition of β-catenin ameliorates neuromuscular, but not systemic, pathology in SMA mice.

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Pharmacological inhibition of β-catenin ameliorates neuromuscular, but n...
(A) Significant improvement on the righting test in early (P6) and late-symptomatic (P9) Taiwanese SMA mice (KO) treated with 10 mg/kg quercetin (Kruskal-Wallis test with Dunn’s post hoc; P3, n = 30 tests Het; n = 27 KO; n = 21 KOQ; P6, n = 31, Het; n = 28 KO; n = 27 KOQ; P9, n = 32, Het; n = 27 KO; n = 36 KOQ). (B and C) Reduced motor neuron loss from spinal cord of quercetin-treated SMA mice at P10. (D) Untreated (left) and a quercetin-treated (right) SMA mice at P10. (E and F) Amelioration of skeletal muscle fibre atrophy in the levator auris longus (LAL) muscle of quercetin-treated SMA mice at P10 (n = 8 muscles Het, n = 9 KO, n = 4 KOQ). (G and H) Reduced NMJ pathology (average number of axonal inputs per NMJ; multiply innervated NMJs are indicated by arrows) in the LAL muscle of quercetin-treated SMA mice at P10 (n = 8 muscles Het, n = 9 KO, n = 4 KOQ). (I) Survival curve for quercetin-treated SMA mice showing no significant difference compared with DMSO-treated controls (P = 0.9897, χ2 test; n = 10 mice DMSO; n = 13 quercetin). (J) Hearts (top) and livers (bottom) from control, SMA (KO DMSO), and quercetin-treated SMA (KO quercetin) mice at P10 showing no improvement in gross pathology. (K and L) UBA1 levels were reduced in all tissues from SMA mice at P10,but β-catenin levels were only correspondingly increased in spinal cord (n > 3 mice per genotype; ANOVA with Tukey’s post-hoc). Scale bars: 200 μm (B), 25 μm (E and G), 5 mm (J). *P < 0.05; **P < 0.01; ***P < 0.001.