Wishart, Thomas M., Mutsaers, Chantal A., Riessland, Markus ORCID: 0000-0003-2592-5045, 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 ORCID: 0000-0001-8548-4734, Morris, Glenn E., Parson, Simon H., Skehel, Paul A., Becker, Thomas ORCID: 0000-0003-2578-0819, Robinson, Iain M., Becker, Catherina G., Wirth, Brunhilde ORCID: 0000-0003-4051-5191 and Gillingwater, Thomas H. (2014). Dysregulation of ubiquitin homeostasis and beta-catenin signaling promote spinal muscular atrophy. J. Clin. Invest., 124 (4). S. 1821 - 1835. ANN ARBOR: AMER SOC CLINICAL INVESTIGATION INC. ISSN 1558-8238

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Wishart, Thomas M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mutsaers, Chantal A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riessland, MarkusUNSPECIFIEDorcid.org/0000-0003-2592-5045UNSPECIFIED
Reimer, Michell M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hunter, GillianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hannam, Marie L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Eaton, Samantha L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fuller, Heidi R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Roche, Sarah L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Somers, EilidhUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Morse, RobertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Young, Philip J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lamont, Douglas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Joshi, AnaghaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hohenstein, PeterUNSPECIFIEDorcid.org/0000-0001-8548-4734UNSPECIFIED
Morris, Glenn E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Parson, Simon H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Skehel, Paul A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ThomasUNSPECIFIEDorcid.org/0000-0003-2578-0819UNSPECIFIED
Robinson, Iain M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, Catherina G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
Gillingwater, Thomas H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-442576
DOI: 10.1172/JCI71318
Journal or Publication Title: J. Clin. Invest.
Volume: 124
Number: 4
Page Range: S. 1821 - 1835
Date: 2014
Publisher: AMER SOC CLINICAL INVESTIGATION INC
Place of Publication: ANN ARBOR
ISSN: 1558-8238
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
SURVIVAL-MOTOR-NEURON; MOUSE MODEL; SMN PROTEIN; NEUROMUSCULAR-JUNCTION; DEFECTS; PATHOLOGY; MUSCLE; DIFFERENTIATION; IMPAIRMENT; PHENOTYPEMultiple languages
Medicine, Research & ExperimentalMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/44257

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