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

Thomas Wishart, Chantal Mutsaers, Markus Reissland, Michell Reimer, Gillian Hunter, Marie Hannam, Samantha Eaton, Heidi Fuller, Sarah Roche, Eilidh Somers, Robert Morse, Philip Young, Douglas Lamont, Matthias Hammerschmidt, Anagha Joshi, Peter Hohenstein, Glenn Morris, Simon Parson, Paul Skehel, Thomas BeckerIain Robinson, Catherina Becker, Brunhilde Wirth, Thomas 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 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.
Original languageEnglish
Pages (from-to)1821-1834
Number of pages14
JournalJournal of Clinical Investigation
Volume124
Issue number4
DOIs
Publication statusPublished - Mar 2014

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Spinal Muscular Atrophy
Catenins
Ubiquitin
Homeostasis
Pathology
Motor Neurons
Zebrafish
Pharmacology
Genetic Suppression
Muscle Development
Ubiquitination
Neurodegenerative Diseases
Drosophila
Spinal Cord
Neurons
Messenger RNA

Keywords

  • spinal muscular atrophy
  • neuromuscular pathology
  • disease pathogenesis

Cite this

Wishart, T., Mutsaers, C., Reissland, M., Reimer, M., Hunter, G., Hannam, M., ... Gillingwater, T. (2014). Dysregulation of ubiquitin homeostasis and ß-catenin signalling promote spinal muscular atrophy. Journal of Clinical Investigation, 124(4), 1821-1834. https://doi.org/10.1172/JCI71318
Wishart, Thomas ; Mutsaers, Chantal ; Reissland, Markus ; Reimer, Michell ; Hunter, Gillian ; Hannam, Marie ; Eaton, Samantha ; Fuller, Heidi ; Roche, Sarah ; Somers, Eilidh ; Morse, Robert ; Young, Philip ; Lamont, Douglas ; Hammerschmidt, Matthias ; Joshi, Anagha ; Hohenstein, Peter ; Morris, Glenn ; Parson, Simon ; Skehel, Paul ; Becker, Thomas ; Robinson, Iain ; Becker, Catherina ; Wirth, Brunhilde ; Gillingwater, Thomas . / Dysregulation of ubiquitin homeostasis and ß-catenin signalling promote spinal muscular atrophy. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 4. pp. 1821-1834.
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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 {\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.",
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Wishart, T, Mutsaers, C, Reissland, M, Reimer, M, Hunter, G, Hannam, M, Eaton, S, Fuller, H, Roche, S, Somers, E, Morse, R, Young, P, Lamont, D, Hammerschmidt, M, Joshi, A, Hohenstein, P, Morris, G, Parson, S, Skehel, P, Becker, T, Robinson, I, Becker, C, Wirth, B & Gillingwater, T 2014, 'Dysregulation of ubiquitin homeostasis and ß-catenin signalling promote spinal muscular atrophy', Journal of Clinical Investigation, vol. 124, no. 4, pp. 1821-1834. https://doi.org/10.1172/JCI71318

Dysregulation of ubiquitin homeostasis and ß-catenin signalling promote spinal muscular atrophy. / Wishart, Thomas ; Mutsaers, Chantal; Reissland, Markus; Reimer, Michell; Hunter, Gillian; Hannam, Marie; Eaton, Samantha; Fuller, Heidi; Roche, Sarah; Somers, Eilidh; Morse, Robert; Young, Philip; Lamont, Douglas; Hammerschmidt, Matthias; Joshi, Anagha; Hohenstein, Peter; Morris, Glenn; Parson, Simon; Skehel, Paul; Becker, Thomas; Robinson, Iain; Becker, Catherina; Wirth, Brunhilde; Gillingwater, Thomas .

In: Journal of Clinical Investigation, Vol. 124, No. 4, 03.2014, p. 1821-1834.

Research output: Contribution to journalArticle

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AU - Wishart, Thomas

AU - Mutsaers, Chantal

AU - Reissland, Markus

AU - Reimer, Michell

AU - Hunter, Gillian

AU - Hannam, Marie

AU - Eaton, Samantha

AU - Fuller, Heidi

AU - Roche, Sarah

AU - Somers, Eilidh

AU - Morse, Robert

AU - Young, Philip

AU - Lamont, Douglas

AU - Hammerschmidt, Matthias

AU - Joshi, Anagha

AU - Hohenstein, Peter

AU - Morris, Glenn

AU - Parson, Simon

AU - Skehel, Paul

AU - Becker, Thomas

AU - Robinson, Iain

AU - Becker, Catherina

AU - Wirth, Brunhilde

AU - Gillingwater, Thomas

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N2 - 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.

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