title: Systemic restoration of UBA1 ameliorates disease in spinal muscular atrophy.
abstract: The autosomal recessive neuromuscular disease spinal muscular atrophy (SMA) is caused by loss of survival motor neuron (SMN) protein. Molecular pathways that are disrupted downstream of SMN therefore represent potentially attractive therapeutic targets for SMA. Here, we demonstrate that therapeutic targeting of ubiquitin pathways disrupted as a consequence of SMN depletion, by increasing levels of one key ubiquitination enzyme (ubiquitin-like modifier activating enzyme 1 [UBA1]), represents a viable approach for treating SMA. Loss of UBA1 was a conserved response across mouse and zebrafish models of SMA as well as in patient induced pluripotent stem cell-derive motor neurons. Restoration of UBA1 was sufficient to rescue motor axon pathology and restore motor performance in SMA zebrafish. Adeno-associated virus serotype 9-UBA1 (AAV9-UBA1) gene therapy delivered systemic increases in UBA1 protein levels that were well tolerated over a prolonged period in healthy control mice. Systemic restoration of UBA1 in SMA mice ameliorated weight loss, increased survival and motor performance, and improved neuromuscular and organ pathology. AAV9-UBA1 therapy was also sufficient to reverse the widespread molecular perturbations in ubiquitin homeostasis that occur during SMA. We conclude that UBA1 represents a safe and effective therapeutic target for the treatment of both neuromuscular and systemic aspects of SMA.
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Powis
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Evangelia
authors.initials: E
authors.lastname: Karyka
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Penelope
authors.initials: P
authors.lastname: Boyd
authors.affiliation: INSERM/UEVE UMR861, Institute for Stem cell Therapy and Exploration of Monogenic Diseases (I-Stem), Corbeil-Essonnes, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Côme
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Jones
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|The Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Eva
authors.initials: E
authors.lastname: Szunyogova
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Ewout Jn
authors.initials: EJ
authors.lastname: Groen
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Department of Life Sciences, Glasgow Caledonian University, Glasgow, United Kingdom.
authors.forename: Gillian
authors.initials: G
authors.lastname: Hunter
authors.affiliation: Centre for Cognitive and Neural Systems.
authors.forename: Derek
authors.initials: D
authors.lastname: Thomson
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|The Roslin Institute, and.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Wishart
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Centre for Neuroregeneration, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Catherina G
authors.initials: CG
authors.lastname: Becker
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|The Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
authors.forename: Simon H
authors.initials: SH
authors.lastname: Parson
authors.affiliation: INSERM/UEVE UMR861, Institute for Stem cell Therapy and Exploration of Monogenic Diseases (I-Stem), Corbeil-Essonnes, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Martinat
authors.affiliation: Sheffield Institute for Translational Neuroscience, University of Sheffield, Sheffield, United Kingdom.
authors.forename: Mimoun
authors.initials: M
authors.lastname: Azzouz
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research and.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, United Kingdom.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
mesh_terms: D000818:Animals; D055785:Gene Knockdown Techniques; D015316:Genetic Therapy; D006706:Homeostasis; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009046:Motor Neurons / Q000166:cytology; D009134:Muscular Atrophy, Spinal / Q000628:therapy*; D044764:Ubiquitin-Activating Enzymes / Q000235:genetics*; D015027:Zebrafish
chemical_list: C471538:UBA1 protein, human; D044764:Ubiquitin-Activating Enzymes