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Polyglutamine-Expanded Huntingtin Exacerbates Age-Related Disruption of Nuclear Integrity and Nucleocytoplasmic Transport.
Gasset-Rosa, Fatima; Chillon-Marinas, Carlos; Goginashvili, Alexander; Atwal, Ranjit Singh; Artates, Jonathan W; Tabet, Ricardos; Wheeler, Vanessa C; Bang, Anne G; Cleveland, Don W; Lagier-Tourenne, Clotilde.
Afiliación
  • Gasset-Rosa F; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Chillon-Marinas C; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Goginashvili A; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Atwal RS; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Artates JW; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
  • Tabet R; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA.
  • Wheeler VC; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Bang AG; Conrad Prebys Center for Chemical Genomics, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
  • Cleveland DW; Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA. Electronic address: dcleveland@ucsd.edu.
  • Lagier-Tourenne C; Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Broad Institute of Harvard University and MIT, Cambridge, MA 02142, USA. Electronic address: clagier-tourenne@mgh.harvard.edu.
Neuron ; 94(1): 48-57.e4, 2017 Apr 05.
Article en En | MEDLINE | ID: mdl-28384474
Onset of neurodegenerative disorders, including Huntington's disease, is strongly influenced by aging. Hallmarks of aged cells include compromised nuclear envelope integrity, impaired nucleocytoplasmic transport, and accumulation of DNA double-strand breaks. We show that mutant huntingtin markedly accelerates all of these cellular phenotypes in a dose- and age-dependent manner in cortex and striatum of mice. Huntingtin-linked polyglutamine initially accumulates in nuclei, leading to disruption of nuclear envelope architecture, partial sequestration of factors essential for nucleocytoplasmic transport (Gle1 and RanGAP1), and intranuclear accumulation of mRNA. In aged mice, accumulation of RanGAP1 together with polyglutamine is shifted to perinuclear and cytoplasmic areas. Consistent with findings in mice, marked alterations in nuclear envelope morphology, abnormal localization of RanGAP1, and nuclear accumulation of mRNA were found in cortex of Huntington's disease patients. Overall, our findings identify polyglutamine-dependent inhibition of nucleocytoplasmic transport and alteration of nuclear integrity as a central component of Huntington's disease.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Envejecimiento / Corteza Cerebral / Neostriado / Transporte Activo de Núcleo Celular / Proteína Huntingtina / Membrana Nuclear Tipo de estudio: Observational_studies / Prognostic_studies Límite: Adult / Aged80 / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Neuron Asunto de la revista: NEUROLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Péptidos / Envejecimiento / Corteza Cerebral / Neostriado / Transporte Activo de Núcleo Celular / Proteína Huntingtina / Membrana Nuclear Tipo de estudio: Observational_studies / Prognostic_studies Límite: Adult / Aged80 / Animals / Female / Humans / Male / Middle aged Idioma: En Revista: Neuron Asunto de la revista: NEUROLOGIA Año: 2017 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos