title: Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice.
abstract: Spinal muscular atrophy results from diminished levels of survival motor neuron (SMN) protein in spinal motor neurons. Low levels of SMN also occur in models of amyotrophic lateral sclerosis (ALS) caused by mutant superoxide dismutase 1 (SOD1) and genetic reduction of SMN levels exacerbates the phenotype of transgenic SOD1(G93A) mice. Here, we demonstrate that SMN protein is significantly reduced in the spinal cords of patients with sporadic ALS. To test the potential of SMN as a modifier of ALS, we overexpressed SMN in 2 different strains of SOD1(G93A) mice. Neuronal overexpression of SMN significantly preserved locomotor function, rescued motor neurons, and attenuated astrogliosis in spinal cords of SOD1(G93A) mice. Despite this, survival was not prolonged, most likely resulting from SMN mislocalization and depletion of gems in motor neurons of symptomatic mice. Our results reveal that SMN upregulation slows locomotor deficit onset and motor neuron loss in this mouse model of ALS. However, disruption of SMN nuclear complexes by high levels of mutant SOD1, even in the presence of SMN overexpression, might limit its survival promoting effects in this specific mouse model. Studies in emerging mouse models of ALS are therefore warranted to further explore the potential of SMN as a modifier of ALS.
authors.affiliation: Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria, Australia; Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia. Electronic address: bradley.turner@florey.edu.au.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Neza
authors.initials: N
authors.lastname: Alfazema
authors.affiliation: Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria, Australia; Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Sheean
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK.
authors.forename: James N
authors.initials: JN
authors.lastname: Sleigh
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK.
authors.forename: Kay E
authors.initials: KE
authors.lastname: Davies
authors.affiliation: Florey Institute of Neuroscience & Mental Health, University of Melbourne, Parkville, Victoria, Australia; Centre for Neuroscience, University of Melbourne, Parkville, Victoria, Australia.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Horne
authors.affiliation: MRC Functional Genomics Unit, Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK; Nuffield Department of Clinical Neurosciences, University of Oxford, John Radcliffe Hospital, Oxford, UK. Electronic address: kevin.talbot@ndcn.ox.ac.uk.
authors.forename: Kevin
authors.initials: K
authors.lastname: Talbot
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics; D000818:Animals; D002470:Cell Survival / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D009043:Motor Activity / Q000235:genetics*; D009046:Motor Neurons / Q000502:physiology*; D009134:Muscular Atrophy, Spinal / Q000235:genetics; D009154:Mutation; D013116:Spinal Cord / Q000166:cytology; D013482:Superoxide Dismutase / Q000235:genetics*; D000072105:Superoxide Dismutase-1; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation
chemical_list: C000606290:SOD1 protein, human; D055533:Survival of Motor Neuron 1 Protein; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1
keywords: Amyotrophic lateral sclerosis; Spinal muscular atrophy; Superoxide dismutase 1; Survival motor neuron