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. DisneyGary J. Bassell, Wilfried Rossoll, Leonard Petrucelli

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


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.

Original languageEnglish (US)
Article number107616
JournalCell reports
Issue number5
StatePublished - May 5 2020


  • ALS
  • C9orf72
  • FTD
  • RAN translation
  • RNA foci
  • SCA36
  • TDP-43
  • mouse
  • poly(GP)
  • poly(PR)

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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