Survival motor neuron protein modulates neuron-specific apoptosis

Douglas A. Kerr, Jocelyn P. Nery, Richard J. Traystman, B. Nelson Chau, J. Marie Hardwick

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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 protects primary neurons and differentiated neuron-like stem cells, but not cultured cell lines from virus-induced apoptotic death. SMN also protects neurons in vivo and increases survival of virus-infected mice. SMN mutants (SMN/Δ7 and SMN-Y272C) found in patients with SMA not only lack antiapoptotic activity but also are potently proapoptotic, causing increased neuronal apoptosis and animal mortality. Full-length SMN is proteolytically processed in brains undergoing apoptosis or after ischemic injury. Mutation of an Asp-252 of SMN abolished cleavage of SMN and increased the antiapoptotic function of full-length SMN in neurons. Taken together, deletions or mutations of the C terminus of SMN that result from proteolysis, splicing (SMN/Δ7), or germ-line mutations (e.g., Y272C), produce a proapoptotic form of SMN that may contribute to neuronal death in SMA and perhaps other neurodegenerative disorders.

Original languageEnglish (US)
Pages (from-to)13312-13317
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number24
StatePublished - Nov 21 2000

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