Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice

NEUROBIOLOGY OF AGING

卷:35

Article

Turner, Bradley J.^1,2  Alfazema, Neza³  Sheean, Rebecca K.^1,2  Sleigh, James N.^3,4  Davies, Kay E.³  Horne, Malcolm K.^1,2  Talbot, Kevin^3,4 

[1] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Parkville, Vic 3010, Australia

[2] Univ Melbourne, Ctr Neurosci, Parkville, Vic 3010, Australia

[3] Univ Oxford, MRC Funct Genom Unit, Dept Physiol Anat & Genet, Oxford, England

[4] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Clin Neurosci, Oxford OX3 9DU, England

关键词: Amyotrophic lateral sclerosis;    Spinal muscular atrophy;    Superoxide dismutase 1;    Survival motor neuron;   

DOI  :  10.1016/j.neurobiolaging.2013.09.030

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Inc. All rights reserved.

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