Survival motor neuron protein modulates neuron-specific apoptosis

Spinal muscular atrophy (SMA) is attributed to mutations in the SMN1 gene, leading to loss of spinal cord motor neurons. The neurotropic Sindbis virus vector system was used to investigate a role for the survival motor neuron (SMN) protein in regulating neuronal apoptosis. Here we show that SMN prot ects primary neurons and differentiated neuron-like stem cells, but not cul tured cell lines from virus-induced apoptotic death. SMN also protects neur ons in vivo and increases survival of virus-infected mice. SMN mutants (SMN Delta7 and SMN-Y272C) found in patients with SMA not only lack antiapoptot ic activity but also are potently proapoptotic, causing increased neuronal apoptosis and animal mortality. Full-length SMN is proteolytically processe d in brains undergoing apoptosis or after ischemic injury. Mutation of an A sp-252 of SMN abolished cleavage of SMM and increased the antiapoptotic fun ction of full-length SMN in neurons. Taken together, deletions or mutations of the C terminus of SMN that result from proteolysis, splicing (SMN Delta 7), or germ-line mutations (e.g., Y272C), produce a proapoptotic form of SM N that may contribute to neuronal death in SMA and perhaps other neurodegen erative disorders.