Synapse Loss in Spinal Muscular Atrophy

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DESCRIPTION (provided by applicant): Proximal Spinal Muscular Atrophy (SMA), a leading genetic cause of infant mortality, is an autosomal recessive disease characterized by the loss of spinal motoneurons, muscle atrophy, and motor impairments with varying disease onset and severity (type I is severe; type II, moderate; type III, mild). Currently, there is no cure for this devastating neurological disease, and the mechanisms of the pathogenesis of SMA are not well understood. In this application, type II SMA-like mouse models (SMN 7 SMA and SMN-Hung SMA) will be used to test a novel concept that reduction of synaptic inputs to motoneurons in the spinal cord, instead of degeneration of neuromuscular junctions, is the key event contributing to motor impairments. Aim 1 will test the hypothesis that the neuromuscular junction is not the major site of defects in type II SMA mice. Light and electron microscopy, as well as electrophysiological analyses, will be applied to examine whether neuromuscular junctions in type II SMA mice at various ages are innervated and function normally, as compared with age- and gender-matched non-SMA littermates. Aim 2 will test the hypothesis that synaptic inputs onto spinal motoneurons are reduced in type II SMA mice. Morphological and biochemical analyses will be used to compare numbers of synaptic puncta on spinal motoneurons and the expression of synaptic vesicle proteins in the spinal cord in type II SMA with those in age- and gender-matched non-SMA littermates. Whether the synapse loss involves synaptic stripping by microglia also will be examined. In addition, whether the synaptic defects are attributed to a decrease or degeneration of synaptic inputs from proprioceptive sensory neurons in the dorsal root ganglion will be investigated. The findings of the proposed research will provide a new concept that SMA is a disease of synapse loss in the spinal motoneurons, rather than degeneration of neuromuscular junctions, as suggested by the prevailing thinking. The proposed research is thus relevant to the development of novel therapies for SMA by targeting synaptic defects in the spinal cord. The new therapeutic concept could be applied to treat other types of motoneuron diseases. PUBLIC HEALTH RELEVANCE: The proposed research is highly relevant to Spinal Muscular Atrophy (SMA), a leading genetic cause of infant death characterized by motor impairments and the loss of motor neurons in the spinal cord. We will use mouse models mimicking type II (moderate) SMA to test a novel concept that synapse loss in spinal motoneurons is a key event contributing to motor impairments. The proposed research would lead to future development of novel therapies for SMA by targeting synaptic defects in the spinal cord.