Hexanucleotide Repeat Expansions in c9FTD/ALS and SCA36 Confer Selective Patterns of Neurodegeneration In Vivo

• DOI: 10.1016/j.celrep.2020.107616
• Publication Date: 2020-05-05T14:40:37Z
• Authors: Tiffany W. Todd; Zachary T. McEachin; Jeannie Chew; Alexander R. Burch; Karen Jansen-West; Jimei Tong; Mei Yue; Yuping Song; Monica Castanedes...; Aishe Kurti; Judith H. Dunmore; John D. Fryer; Yong-Jie Zhang; Beatriz San Millan; Susana Teijeira B...; Manuel Arias; Dennis Dickson; Tania F. Gendron; María-Jesús Sobrido; Matthew D. Disney; Gary J. Bassell; Wilfried Rossoll; Leonard Petrucelli
• Keywords: C9ORF72

A G4C2 hexanucleotide repeat expansion in an intron of C9orf72 is the most common cause frontal temporal dementia and amyotrophic lateral sclerosis (c9FTD/ALS). remarkably similar intronic TG3C2 associated with spinocerebellar ataxia 36 (SCA36). Both expansions are widely expressed, form RNA foci, can undergo repeat-associated non-ATG (RAN) translation to dipeptide proteins (DPRs). Yet, these diseases result degeneration distinct subsets neurons. We show that expression mice sufficient recapitulate unique features each disease, including this selective neuronal vulnerability. Furthermore, only induces formation aberrant stress granules pTDP-43 inclusions. Overall, our results demonstrate pathomechanisms responsible for disease intrinsic individual sequence, highlighting importance sequence-specific RNA-mediated toxicity disorder.