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Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36.
McEachin, Zachary T; Gendron, Tania F; Raj, Nisha; García-Murias, María; Banerjee, Anwesha; Purcell, Ryan H; Ward, Patricia J; Todd, Tiffany W; Merritt-Garza, Megan E; Jansen-West, Karen; Hales, Chadwick M; García-Sobrino, Tania; Quintáns, Beatriz; Holler, Christopher J; Taylor, Georgia; San Millán, Beatriz; Teijeira, Susana; Yamashita, Toru; Ohkubo, Ryuichi; Boulis, Nicholas M; Xu, Chongchong; Wen, Zhexing; Streichenberger, Nathalie; Fogel, Brent L; Kukar, Thomas; Abe, Koji; Dickson, Dennis W; Arias, Manuel; Glass, Jonathan D; Jiang, Jie; Tansey, Malú G; Sobrido, María-Jesús; Petrucelli, Leonard; Rossoll, Wilfried; Bassell, Gary J.
Afiliação
  • McEachin ZT; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA. El
  • Gendron TF; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Raj N; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • García-Murias M; Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
  • Banerjee A; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • Purcell RH; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • Ward PJ; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • Todd TW; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Merritt-Garza ME; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • Jansen-West K; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Hales CM; Department of Neurology, Emory University, Atlanta, GA 30322, USA.
  • García-Sobrino T; Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
  • Quintáns B; Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
  • Holler CJ; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
  • Taylor G; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
  • San Millán B; Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; Pathology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain.
  • Teijeira S; Rare Diseases and Pediatric Medicine Research Group, Galicia Sur Health Research Institute (IIS Galicia Sur), SERGAS-UVIGO, Vigo, Spain; Pathology Department, Complexo Hospitalario Universitario de Vigo (CHUVI), SERGAS, Vigo, Spain.
  • Yamashita T; Department of Neurology, Okayama University, Okayama, Japan.
  • Ohkubo R; Department of Neurology, Fujimoto General Hospital, Miyazaki, Japan.
  • Boulis NM; Department of Neurosurgery, Emory University, Atlanta, GA 30322, USA.
  • Xu C; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta, GA 30322, USA.
  • Wen Z; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Psychiatry & Behavioral Sciences, Emory University, Atlanta,
  • Streichenberger N; Hospices Civils de Lyon, Lyon, France; Université Claude Bernard Lyon, Lyon, France; Institut NeuroMyogène CNRS UMR 5310.
  • Fogel BL; Department of Neurology & Human Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
  • Kukar T; Department of Neurology, Emory University, Atlanta, GA 30322, USA; Department of Pharmacology & Chemical Biology, Emory University, Atlanta, GA 30322, USA.
  • Abe K; Department of Neurology, Okayama University, Okayama, Japan.
  • Dickson DW; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Arias M; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain; Department of Neurology, Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
  • Glass JD; Department of Neurology, Emory University, Atlanta, GA 30322, USA.
  • Jiang J; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA.
  • Tansey MG; Department of Neuroscience, University of Florida, Gainesville, FL 32607, USA; Center for Translational Research in Neurodegenerative Disease, University of Florida, Gainesville, FL 32607, USA; Norman Fixel Institute for Neurological Diseases, University of Florida, Gainesville, FL 32607, USA.
  • Sobrido MJ; Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain; Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain.
  • Petrucelli L; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Rossoll W; Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Mayo Clinic Graduate School of Biomedical Sciences, Mayo Clinic, Jacksonville, FL 32224, USA.
  • Bassell GJ; Department of Cell Biology, Emory University, Atlanta, GA 30322, USA; Laboratory for Translational Cell Biology, Emory University, Atlanta, GA 30322, USA; Wallace H. Coulter Graduate Program in Biomedical Engineering, Georgia Institute of Technology & Emory University, Atlanta, GA 30332, USA; De
Neuron ; 107(2): 292-305.e6, 2020 07 22.
Article em En | MEDLINE | ID: mdl-32375063
ABSTRACT
GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ataxias Espinocerebelares / Dipeptídeos / Proteínas Mutantes Quiméricas / Demência Frontotemporal / Proteína C9orf72 / Esclerose Lateral Amiotrófica Limite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Neuron Assunto da revista: NEUROLOGIA Ano de publicação: 2020 Tipo de documento: Article
Texto completo
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ataxias Espinocerebelares / Dipeptídeos / Proteínas Mutantes Quiméricas / Demência Frontotemporal / Proteína C9orf72 / Esclerose Lateral Amiotrófica Limite: Animals / Female / Humans / Pregnancy Idioma: En Revista: Neuron Assunto da revista: NEUROLOGIA Ano de publicação: 2020 Tipo de documento: Article