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Disulfide cross-linked multimers of TDP-43 and spinal motoneuron loss in a TDP-43A315T ALS/FTD mouse model.
Bargsted, Leslie; Medinas, Danilo B; Martínez Traub, Francisca; Rozas, Pablo; Muñoz, Natalia; Nassif, Melissa; Jerez, Carolina; Catenaccio, Alejandra; Court, Felipe A; Hetz, Claudio; Matus, Soledad.
Afiliação
  • Bargsted L; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
  • Medinas DB; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.
  • Martínez Traub F; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
  • Rozas P; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
  • Muñoz N; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.
  • Nassif M; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
  • Jerez C; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
  • Catenaccio A; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.
  • Court FA; Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago, Chile.
  • Hetz C; Biomedical Neuroscience Institute, Faculty of Medicine, University of Chile, Santiago, Chile.
  • Matus S; Geroscience Center for Brain Health and Metabolism (GERO), Santiago, Chile.
Sci Rep ; 7(1): 14266, 2017 10 27.
Article em En | MEDLINE | ID: mdl-29079747
Tar DNA binding protein 43 (TDP-43) is the principal component of ubiquitinated protein inclusions present in nervous tissue of most cases of both amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Previous studies described a TDP-43A315T transgenic mouse model that develops progressive motor dysfunction in the absence of protein aggregation or significant motoneuron loss, questioning its validity to study ALS. Here we have further characterized the course of the disease in TDP-43A315T mice using a battery of tests and biochemical approaches. We confirmed that TDP-43 mutant mice develop impaired motor performance, accompanied by progressive body weight loss. Significant differences were observed in life span between genders, where females survived longer than males. Histopathological analysis of the spinal cord demonstrated a significant motoneurons loss, accompanied by axonal degeneration, astrogliosis and microglial activation. Importantly, histopathological alterations observed in TDP-43 mutant mice were similar to some characteristic changes observed in mutant SOD1 mice. Unexpectedly, we identified the presence of different species of disulfide-dependent TDP-43 aggregates in cortex and spinal cord tissue. Overall, this study indicates that TDP-43A315T transgenic mice develop key features resembling key aspects of ALS, highlighting its relevance to study disease pathogenesis.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Medula Espinal / Dissulfetos / Proteínas de Ligação a DNA / Multimerização Proteica / Demência Frontotemporal / Esclerose Lateral Amiotrófica / Neurônios Motores Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Sci Rep Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Chile País de publicação: Reino Unido
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Medula Espinal / Dissulfetos / Proteínas de Ligação a DNA / Multimerização Proteica / Demência Frontotemporal / Esclerose Lateral Amiotrófica / Neurônios Motores Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Sci Rep Ano de publicação: 2017 Tipo de documento: Article País de afiliação: Chile País de publicação: Reino Unido