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

• Published in: Cell reports (Cambridge) Vol. 31; no. 5; p. 107616
• Main Authors: Todd, Tiffany W., McEachin, Zachary T., Chew, Jeannie, Burch, Alexander R., Jansen-West, Karen, Tong, Jimei, Yue, Mei, Song, Yuping, Castanedes-Casey, Monica, Kurti, Aishe, Dunmore, Judith H., Fryer, John D., Zhang, Yong-Jie, San Millan, Beatriz, Teijeira Bautista, Susana, Arias, Manuel, Dickson, Dennis, Gendron, Tania F., Sobrido, María-Jesús, Disney, Matthew D., Bassell, Gary J., Rossoll, Wilfried, Petrucelli, Leonard
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05-05-2020; Elsevier
• Subjects: ALS; C9orf72; FTD; mouse; poly(GP); poly(PR); RAN translation; RNA foci; SCA36; TDP-43; mouse; RAN translation; poly(PR); SCA36; TDP-43; FTD; ALS; poly(GP); RNA foci; C9orf72
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107616

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.
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•NOP56-(TG3C2)62 and C9orf72-(G4C2)66 repeats confer distinct phenotypes in mice•NOP56-(TG3C2)62 induces cerebellar degeneration akin to SCA36•RNA foci and RAN translation in the SCA36 mice resemble human pathologies•TDP-43 proteinopathy and aberrant stress granules are unique to C9orf72-G4C2
c9FTD/ALS and SCA36 are distinct diseases associated with similar hexanucleotide repeat expansions: G4C2 versus TG3C2. Todd et al. show that expressing these repeats in mice is sufficient to recapitulate each disease. The pathology and selective neurodegeneration characteristic of each disorder are therefore due to pathomechanisms intrinsic to each repeat sequence.