CCG•CGG interruptions in high‐penetrance SCA8 families increase RAN translation and protein toxicity
Year: 2021
Type: article
Study design: Observational Study
Abstract: Spinocerebellar ataxia type 8 (SCA8), a dominantly inherited neurodegenerative disorder caused by a CTG•CAG expansion, is unusual because most individuals that carry the mutation do not develop ataxia. To understand the variable penetrance of SCA8, we studied the molecular differences between highly penetrant families and more common sporadic cases (82%) using a large cohort of SCA8 families (n = 77). We show that repeat expansion mutations from individuals with multiple affected family members have CCG•CGG interruptions at a higher frequency than sporadic SCA8 cases and that the number of CCG•CGG interruptions correlates with age at onset. At the molecular level, CCG•CGG interruptions increase RNA hairpin stability, and in cell culture experiments, increase p-eIF2α and polyAla and polySer RAN protein levels. Additionally, CCG•CGG interruptions, which encode arginine interruptions in the polyGln frame, increase toxicity of the resulting proteins. In summary, SCA8 CCG•CGG interruptions increase polyAla and polySer RAN protein levels, polyGln protein toxicity, and disease penetrance and provide novel insight into the molecular differences between SCA8 families with high vs. low disease penetrance.
Source: EMBO Molecular Medicine
Authors: Barbara A Perez, Hannah K Shorrock, Monica Banez‐Coronel, Tao Zu, Lisa EL Romano, Lauren A Laboissonniere, Tammy Reid, Yoshio Ikeda, Kaalak Reddy, Christopher M Gomez, Thomas Bird, Tetsuo Ashizawa, Lawrence J Schut, Alfredo Brusco, J Andrew Berglund, Lis F Hasholt, Jorgen E Nielsen, SH Subramony, Laura PW Ranum
Institutions: University of Florida, Gunma University, University at Albany, State University of New York, University of Chicago, University of Washington, VA Puget Sound Health Care System, Houston Methodist, University of Minnesota, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, University of Turin, University of Copenhagen, Rigshospitalet
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,000
Awards: G1541068835, G4351099770, Therapeutic development of microsatellite repeat expansion disorder focusing on the transcriptional mechanism, G6508420926, G6546474855, G6939716944, Senator Paul D. Wellstone Muscular Dystrophy Specialized Research Center, G9000313859, Interdisciplinary Training in Movement Disorders and Neurorestoration, Molecular effects of metformin, PKR and TBI on C9orf72 ALS/FTD, G979817671
OpenAlex ID: W3206957765