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 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 (SMNDelta7 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 (SMNDelta7), 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.
Kerr
D A
DA
Departments of Neurology, Molecular Microbiology and Immunology, Anesthesiology and Critical Care Medicine, and Pharmacology and Molecular Sciences, The Johns Hopkins Schools of Medicine and Public Health, Baltimore, MD 21205, USA.
Nery
J P
JP
Traystman
R J
RJ
Chau
B N
BN
Hardwick
J M
JM
D018354:Alphavirus Infections / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001921:Brain / Q000166:cytology* / Q000473:pathology; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D006224:Cricetinae; D017362:Cyclic AMP Response Element-Binding Protein; D006801:Humans; D051379:Mice; D009134:Muscular Atrophy, Spinal / Q000235:genetics / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D014176:Protein Biosynthesis; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; D017384:Sequence Deletion; D012845:Sindbis Virus / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000502:physiology; D055533:Survival of Motor Neuron 1 Protein
D017362:Cyclic AMP Response Element-Binding Protein; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein