title: Enhancing survival motor neuron expression extends lifespan and attenuates neurodegeneration in mutant TDP-43 mice.
abstract: Defects in the RNA-binding proteins survival motor neuron (SMN) and TAR DNA-binding protein 43 (TDP-43) cause progressive motor neuron degeneration in spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. While low levels of SMN protein in motor neurons result in SMA, recent studies implicate abnormal SMN levels and function in ALS pathogenesis. Here, we determine that SMN protein is upregulated early and progressively in spinal and cortical motor neurons of male transgenic mutant TDP-43A315Tmice. Cytoplasmic SMN aggregates that contain TDP-43 and HuR were identified in motor neurons of TDP-43A315Tmice, consistent with the incorporation of SMN into stress granules. To test the impact of augmenting SMN levels in TDP-43 proteinopathy, we demonstrate that neuronal overexpression of human SMN in TDP-43A315Tmice delayed symptom onset and prolonged survival. SMN upregulation also countered motor neuron degeneration, attenuated activation of astrocytes and microglia and restored AMP kinase activation in spinal cords of TDP-43A315Tmice. We also reveal that expression of another factor conferring motor neuron vulnerability, androgen receptor (AR), is reduced in spinal cords of male TDP-43A315Tmice. These results establish that SMN overexpression in motor neurons slows disease onset and outcome by ameliorating pathological signs in this model of mutant TDP-43-mediated ALS. Further approaches to augment SMN levels using pharmacological or gene therapy agents may therefore be warranted in ALS. Our data also reinforce a novel potential link between ALS and spinal bulbar muscular atrophy (SBMA), another motor neurodegenerative disease mediated by reduced AR function in motor neurons.
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Nirma D
authors.initials: ND
authors.lastname: Perera
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Rebecca K
authors.initials: RK
authors.lastname: Sheean
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Crouch
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: White
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Malcolm K
authors.initials: MK
authors.lastname: Horne
authors.affiliation: The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria 3052, Australia bradley.turner@florey.edu.au.
authors.forename: Bradley J
authors.initials: BJ
authors.lastname: Turner
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D003593:Cytoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009046:Motor Neurons / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics; D055533:Survival of Motor Neuron 1 Protein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; D055533:Survival of Motor Neuron 1 Protein; C578077:Tardbp protein, mouse