Cell Reports (May 2020)
Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo
- Tiffany W. Todd,
- Zachary T. McEachin,
- Jeannie Chew,
- Alexander R. Burch,
- Karen Jansen-West,
- Jimei Tong,
- Mei Yue,
- Yuping Song,
- Monica Castanedes-Casey,
- Aishe Kurti,
- Judith H. Dunmore,
- John D. Fryer,
- Yong-Jie Zhang,
- Beatriz San Millan,
- Susana Teijeira Bautista,
- Manuel Arias,
- Dennis Dickson,
- Tania F. Gendron,
- María-Jesús Sobrido,
- Matthew D. Disney,
- Gary J. Bassell,
- Wilfried Rossoll,
- Leonard Petrucelli
Affiliations
- Tiffany W. Todd
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Zachary T. McEachin
- 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
- Jeannie Chew
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Alexander R. Burch
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Karen Jansen-West
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Jimei Tong
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Mei Yue
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Yuping Song
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Monica Castanedes-Casey
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Aishe Kurti
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Judith H. Dunmore
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- John D. Fryer
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Yong-Jie Zhang
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Beatriz San Millan
- 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
- Susana Teijeira Bautista
- 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
- Manuel Arias
- 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
- Dennis Dickson
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- Tania F. Gendron
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA
- María-Jesús Sobrido
- Neurogenetics Research Group, Instituto de Investigación Sanitaria (IDIS), Hospital Clínico Universitario, SERGAS, Santiago de Compostela, Spain; Centro de Investigación Biomédica en red de Enfermedades Raras (CIBERER), Santiago de Compostela, Spain
- Matthew D. Disney
- Department of Chemistry, The Scripps Research Institute, Scripps Florida, Jupiter, FL 33458, USA
- Gary J. Bassell
- 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
- Wilfried Rossoll
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Corresponding author
- Leonard Petrucelli
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA; Corresponding author
- Journal volume & issue
-
Vol. 31,
no. 5
Abstract
Summary: A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause of frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). A remarkably similar intronic TG3C2 repeat expansion is associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, and can undergo repeat-associated non-ATG (RAN) translation to form similar dipeptide repeat proteins (DPRs). Yet, these diseases result in the degeneration of distinct subsets of neurons. We show that the expression of these repeat expansions in mice is sufficient to recapitulate the unique features of each disease, including this selective neuronal vulnerability. Furthermore, only the G4C2 repeat induces the formation of aberrant stress granules and pTDP-43 inclusions. Overall, our results demonstrate that the pathomechanisms responsible for each disease are intrinsic to the individual repeat sequence, highlighting the importance of sequence-specific RNA-mediated toxicity in each disorder.
