SMN-dependent intrinsic defects in Schwann cells in mouse models of spinal muscular atrophy

Abstract

Low levels of survival of motor neuron (SMN) protein lead to spinal muscular atrophy (SMA). The major pathological hallmark of SMA is a loss of lower motor neurons from spinal cord and peripheral nerve. However, recent studies have revealed pathological changes in other cells and tissues of the neuromuscular system. Here, we demonstrate intrinsic, SMN-dependent defects in Schwann cells in SMA. Myelination in intercostal nerves was perturbed at early- and late-symptomatic stages of disease in two mouse models of SMA. Similarly, maturation of axo-glial interactions at paranodeswasdisrupted inSMAmice. In contrast, myelination of motor axons in the corticospinal tract of the spinal cord occurred normally. Schwann cells isolated fromSMA mice had significantly reduced levels ofSMNand failed to express key myelin proteins following differentiation, likely due to perturbations in protein translation and/or stability rather than transcriptional defects. Myelin protein expressionwasrestored inSMASchwanncells following transfection withanSMNconstruct. Co-cultures of healthy neurons with diseased Schwann cells revealed deficientmyelination, suggestive of intrinsic defects in Schwann cells, as well as reduced neurite stability. Alongside myelination defects, SMA Schwann cells failed to express normal levels of key extracellular matrix proteins, including laminina2.Weconclude thatSchwanncells require high levels ofSMNprotein for their normal development and function in vivo, with reduced levels ofSMN resulting in myelination defects, delayed maturation of axo-glial interactions and abnormal composition of extracellular matrix in peripheral nerve. © The Author 2013. Published by Oxford University Press. All rights reserved.