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Pre-natal manifestation of systemic developmental abnormalities in spinal muscular atrophy.
Motyl, Anna A L; Faller, Kiterie M E; Groen, Ewout J N; Kline, Rachel A; Eaton, Samantha L; Ledahawsky, Leire M; Chaytow, Helena; Lamont, Douglas J; Wishart, Thomas M; Huang, Yu-Ting; Gillingwater, Thomas H.
Afiliação
  • Motyl AAL; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.
  • Faller KME; Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK.
  • Groen EJN; Royal (Dick) School of Veterinary Studies, University of Edinburgh, Edinburgh EH25 9RG, UK.
  • Kline RA; UMC Utrecht Brain Center, University Medical Center, Utrecht 3584 CG, The Netherlands.
  • Eaton SL; Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK.
  • Ledahawsky LM; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
  • Chaytow H; Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK.
  • Lamont DJ; The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian EH25 9RG, UK.
  • Wishart TM; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.
  • Huang YT; Euan MacDonald Centre for Motor Neurone Disease Research, University of Edinburgh, Edinburgh EH16 4SB, UK.
  • Gillingwater TH; Edinburgh Medical School: Biomedical Sciences, University of Edinburgh, Edinburgh EH8 9XD, UK.
Hum Mol Genet ; 29(16): 2674-2683, 2020 09 29.
Article em En | MEDLINE | ID: mdl-32644120
Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in survival motor neuron 1 (SMN1). SMN-restoring therapies have recently emerged; however, preclinical and clinical studies revealed a limited therapeutic time window and systemic aspects of the disease. This raises a fundamental question of whether SMA has presymptomatic, developmental components to disease pathogenesis. We have addressed this by combining micro-computed tomography (µCT) and comparative proteomics to examine systemic pre-symptomatic changes in a prenatal mouse model of SMA. Quantitative µCT analyses revealed that SMA embryos were significantly smaller than littermate controls, indicative of general developmental delay. More specifically, cardiac ventricles were smaller in SMA hearts, whilst liver and brain remained unaffected. In order to explore the molecular consequences of SMN depletion during development, we generated comprehensive, high-resolution, proteomic profiles of neuronal and non-neuronal organs in SMA mouse embryos. Significant molecular perturbations were observed in all organs examined, highlighting tissue-specific prenatal molecular phenotypes in SMA. Together, our data demonstrate considerable systemic changes at an early, presymptomatic stage in SMA mice, revealing a significant developmental component to SMA pathogenesis.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Atrofia Muscular Espinal / Proteína 1 de Sobrevivência do Neurônio Motor / Miocárdio Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Atrofia Muscular Espinal / Proteína 1 de Sobrevivência do Neurônio Motor / Miocárdio Tipo de estudo: Diagnostic_studies / Prognostic_studies Limite: Animals / Humans Idioma: En Ano de publicação: 2020 Tipo de documento: Article