title: Hypothermia improves disease manifestations in SMA mice via SMN augmentation.
abstract: Spinal muscular atrophy (SMA) is a progressive motor neuron disease caused by a deficiency of survival motor neuron (SMN) protein. In this study, we evaluated the efficacy of intermittent transient hypothermia in a mouse model of SMA. SMA mice were exposed to ice for 50 s to achieve transient hypothermia (below 25°C) daily beginning on postnatal day 1. Neonatal SMA mice (Smn(-/-)SMN2(+/-)) who received daily transient hypothermia exhibited reduced motor neuron degeneration and muscle atrophy and preserved the architecture of neuromuscular junction when compared with untreated controls at day 8 post-treatment. Daily hypothermia also prolonged the lifespan, increased body weight and improved motor coordination in SMA mice. Quantitative polymerase chain reaction and western blot analyses showed that transient hypothermia led to an increase in SMN transcript and protein levels in the spinal cord and brain. In in vitro studies using an SMN knockdown motor neuron-like cell-line, transient hypothermia increased intracellular SMN protein expression and length of neurites, confirming the direct effect of hypothermia on motor neurons. These data indicate that the efficacy of intermittent transient hypothermia in improving outcome in an SMA mouse model may be mediated, in part, via an upregulation of SMN levels in the motor neurons.
authors.affiliation: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan, milikai@ntuh.gov.tw.
authors.forename: Li-Kai
authors.initials: LK
authors.lastname: Tsai
authors.affiliation: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Chien-Lin
authors.initials: CL
authors.lastname: Chen
authors.affiliation: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei 100, Taiwan.
authors.forename: Yi-Chieh
authors.initials: YC
authors.lastname: Tsai
authors.affiliation: Marine Research Station, Institute of Cellular and Organismic Biology, Academia Sinica, 23-10 Dahuen Road, Jiaushi, Ilan 262, Taiwan and.
authors.forename: Chen-Hung
authors.initials: CH
authors.lastname: Ting
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Yin-Hsio
authors.initials: YH
authors.lastname: Chien
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Ni-Chong
authors.initials: NC
authors.lastname: Lee
authors.affiliation: Department of Medical Genetics, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D007036:Hypothermia, Induced / Q000379:methods*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D009469:Neuromuscular Junction / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D055533:Survival of Motor Neuron 1 Protein / Q000378:metabolism*; D055540:Survival of Motor Neuron 2 Protein / Q000378:metabolism*
chemical_list: D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein