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Dysregulation of Mdm2 and Mdm4 alternative splicing underlies motor neuron death in spinal muscular atrophy.
Van Alstyne, Meaghan; Simon, Christian M; Sardi, S Pablo; Shihabuddin, Lamya S; Mentis, George Z; Pellizzoni, Livio.
Afiliación
  • Van Alstyne M; Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA.
  • Simon CM; Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
  • Sardi SP; Center for Motor Neuron Biology and Disease, Columbia University, New York, New York 10032, USA.
  • Shihabuddin LS; Department of Pathology and Cell Biology, Columbia University, New York, New York 10032, USA.
  • Mentis GZ; Neuroscience Therapeutic Area, Sanofi, Framingham, Massachusetts 01701, USA.
  • Pellizzoni L; Neuroscience Therapeutic Area, Sanofi, Framingham, Massachusetts 01701, USA.
Genes Dev ; 32(15-16): 1045-1059, 2018 08 01.
Article en En | MEDLINE | ID: mdl-30012555
Ubiquitous deficiency in the survival motor neuron (SMN) protein causes death of motor neurons-a hallmark of the neurodegenerative disease spinal muscular atrophy (SMA)-through poorly understood mechanisms. Here, we show that the function of SMN in the assembly of spliceosomal small nuclear ribonucleoproteins (snRNPs) regulates alternative splicing of Mdm2 and Mdm4, two nonredundant repressors of p53. Decreased inclusion of critical Mdm2 and Mdm4 exons is most prominent in SMA motor neurons and correlates with both snRNP reduction and p53 activation in vivo. Importantly, increased skipping of Mdm2 and Mdm4 exons regulated by SMN is necessary and sufficient to synergistically elicit robust p53 activation in wild-type mice. Conversely, restoration of full-length Mdm2 and Mdm4 suppresses p53 induction and motor neuron degeneration in SMA mice. These findings reveal that loss of SMN-dependent regulation of Mdm2 and Mdm4 alternative splicing underlies p53-mediated death of motor neurons in SMA, establishing a causal link between snRNP dysfunction and neurodegeneration.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Atrofia Muscular Espinal / Proteínas Proto-Oncogénicas / Empalme Alternativo / Proteínas Proto-Oncogénicas c-mdm2 / Neuronas Motoras Límite: Animals Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Atrofia Muscular Espinal / Proteínas Proto-Oncogénicas / Empalme Alternativo / Proteínas Proto-Oncogénicas c-mdm2 / Neuronas Motoras Límite: Animals Idioma: En Revista: Genes Dev Asunto de la revista: BIOLOGIA MOLECULAR Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos