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.SMAmicewere 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.