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C9ORF72 poly(GA) aggregates sequester and impair HR23 and nucleocytoplasmic transport proteins.
Zhang, Yong-Jie; Gendron, Tania F; Grima, Jonathan C; Sasaguri, Hiroki; Jansen-West, Karen; Xu, Ya-Fei; Katzman, Rebecca B; Gass, Jennifer; Murray, Melissa E; Shinohara, Mitsuru; Lin, Wen-Lang; Garrett, Aliesha; Stankowski, Jeannette N; Daughrity, Lillian; Tong, Jimei; Perkerson, Emilie A; Yue, Mei; Chew, Jeannie; Castanedes-Casey, Monica; Kurti, Aishe; Wang, Zizhao S; Liesinger, Amanda M; Baker, Jeremy D; Jiang, Jie; Lagier-Tourenne, Clotilde; Edbauer, Dieter; Cleveland, Don W; Rademakers, Rosa; Boylan, Kevin B; Bu, Guojun; Link, Christopher D; Dickey, Chad A; Rothstein, Jeffrey D; Dickson, Dennis W; Fryer, John D; Petrucelli, Leonard.
Afiliação
  • Zhang YJ; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Gendron TF; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Grima JC; Department of Neurology, School of Medicine, Johns Hopkins University, Maryland, USA.
  • Sasaguri H; Brain Science Institute, School of Medicine, Johns Hopkins University, Maryland, USA.
  • Jansen-West K; Department of Neuroscience, School of Medicine, Johns Hopkins University, Maryland, USA.
  • Xu YF; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Katzman RB; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Gass J; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Murray ME; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Shinohara M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Lin WL; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Garrett A; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Stankowski JN; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Daughrity L; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Tong J; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Perkerson EA; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Yue M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Chew J; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Castanedes-Casey M; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Kurti A; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Wang ZS; Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.
  • Liesinger AM; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Baker JD; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Jiang J; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Lagier-Tourenne C; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Edbauer D; Department of Molecular Medicine, College of Medicine, Byrd Alzheimer's Institute, University of South Florida, Tampa, Florida, USA.
  • Cleveland DW; Ludwig Institute, University of California at San Diego, La Jolla, California, USA.
  • Rademakers R; Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
  • Boylan KB; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • Bu G; Institute for Metabolic Biochemistry, Ludwig Maximilians University Munich, Munich, Germany.
  • Link CD; Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
  • Dickey CA; Ludwig Institute, University of California at San Diego, La Jolla, California, USA.
  • Rothstein JD; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA.
  • Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
  • Fryer JD; Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA.
  • Petrucelli L; Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA.
Nat Neurosci ; 19(5): 668-677, 2016 05.
Article em En | MEDLINE | ID: mdl-26998601
ABSTRACT
Neuronal inclusions of poly(GA), a protein unconventionally translated from G4C2 repeat expansions in C9ORF72, are abundant in patients with frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) caused by this mutation. To investigate poly(GA) toxicity, we generated mice that exhibit poly(GA) pathology, neurodegeneration and behavioral abnormalities reminiscent of FTD and ALS. These phenotypes occurred in the absence of TDP-43 pathology and required poly(GA) aggregation. HR23 proteins involved in proteasomal degradation and proteins involved in nucleocytoplasmic transport were sequestered by poly(GA) in these mice. HR23A and HR23B similarly colocalized to poly(GA) inclusions in C9ORF72 expansion carriers. Sequestration was accompanied by an accumulation of ubiquitinated proteins and decreased xeroderma pigmentosum C (XPC) levels in mice, indicative of HR23A and HR23B dysfunction. Restoring HR23B levels attenuated poly(GA) aggregation and rescued poly(GA)-induced toxicity in neuronal cultures. These data demonstrate that sequestration and impairment of nuclear HR23 and nucleocytoplasmic transport proteins is an outcome of, and a contributor to, poly(GA) pathology.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas / Proteínas de Transporte / Fatores de Troca do Nucleotídeo Guanina / Proteínas de Ligação a DNA / Neurônios Limite: Animals / Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Proteínas / Proteínas de Transporte / Fatores de Troca do Nucleotídeo Guanina / Proteínas de Ligação a DNA / Neurônios Limite: Animals / Humans Idioma: En Revista: Nat Neurosci Assunto da revista: NEUROLOGIA Ano de publicação: 2016 Tipo de documento: Article País de afiliação: Estados Unidos