title: Restoration of SMN in Schwann cells reverses myelination defects and improves neuromuscular function in spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a neuromuscular disease caused by low levels of SMN protein, primarily affecting lower motor neurons. Recent evidence from SMA and related conditions suggests that glial cells can influence disease severity. Here, we investigated the role of glial cells in the peripheral nervous system by creating SMA mice selectively overexpressing SMN in myelinating Schwann cells (Smn-/-;SMN2tg/0;SMN1SC). Restoration of SMN protein levels restricted solely to Schwann cells reversed myelination defects, significantly improved neuromuscular function and ameliorated neuromuscular junction pathology in SMA mice. However, restoration of SMN in Schwann cells had no impact on motor neuron soma loss from the spinal cord or ongoing systemic and peripheral pathology. This study provides evidence for a defined, intrinsic contribution of glial cells to SMA disease pathogenesis and suggests that therapies designed to include Schwann cells in their target tissues are likely to be required in order to rescue myelination defects and associated disease symptoms.
authors.affiliation: Department of Life Sciences, School of Health and Life Sciences, Glasgow Caledonian University, Glasgow G4 0BA, UK, T.Gillingwater@ed.ac.uk.|Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Gillian
authors.initials: G
authors.lastname: Hunter
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK, T.Gillingwater@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: Powis
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK, T.Gillingwater@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Ross A
authors.initials: RA
authors.lastname: Jones
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK, T.Gillingwater@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Ewout J N
authors.initials: EJ
authors.lastname: Groen
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK, T.Gillingwater@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Shorrock
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK, T.Gillingwater@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Lane
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK, T.Gillingwater@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Yinan
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, EH16 4SB, UK T.Gillingwater@ed.ac.uk.
authors.forename: Diane L
authors.initials: DL
authors.lastname: Sherman
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, EH16 4SB, UK T.Gillingwater@ed.ac.uk.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.affiliation: Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh, EH16 4SB, UK, T.Gillingwater@ed.ac.uk.|Centre for Integrative Physiology, University of Edinburgh, Edinburgh, EH8 9XD, UK and.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Gillingwater
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D009134:Muscular Atrophy, Spinal / Q000378:metabolism; D009186:Myelin Sheath / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology; D009457:Neuroglia / Q000378:metabolism*; D009468:Neuromuscular Diseases / Q000473:pathology; D009469:Neuromuscular Junction / Q000378:metabolism; D012583:Schwann Cells / Q000378:metabolism; D013116:Spinal Cord / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics* / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000597152:SMN2 protein, mouse; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein