biostudies-literatureBhatt NAmerican Heart AssociationMitchell Center for Neurodegenerative Diseases, University of Texas Medical BranchNational Institutes of HealthGillson Longenbaugh Foundation105628https://www.ebi.ac.uk/biostudies/studies/S-EPMC10844744biostudies-literatureUnknown300(2)Hexanucleotide repeat expansion in C9orf72 is one of the most common causes of amyotrophic lateral sclerosis and frontotemporal dementia. The hexanucleotide expansion, formed by GGGGCC (G4C2) repeats, leads to the production of five dipeptide protein repeats (DPRs) via repeat-associated non-AUG translation. Among the five dipeptide repeats, Gly-Arg, Pro-Arg, and Gly-Ala form neuronal inclusions that contain aggregates of the peptides. Several studies have attempted to model DPR-associated toxicity using various repeat lengths, which suggests a unique conformation that is cytotoxic and is independent of the repeat length. However, the structural characteristics of DPR aggregates have yet to be determined. Increasing evidence suggests that soluble species, such as oligomers, are the main cauThe Journal of biological chemistryC9orf72-associated dipeptide protein repeats form A11-positive oligomers in amyotrophic lateral sclerosis and frontotemporal dementia.PMC10844744R01NS09455717CSA33620007R01AG060718RFA1AG055771R01AG054025Sengupta UGandhi SPuangmalai NJerez CKayed RBhatt NKidd MfalseC9orf72-associated dipeptide protein repeats form A11-positive oligomers in amyotrophic lateral sclerosis and frontotemporal dementia.Hexanucleotide repeat expansion in C9orf72 is one of the most common causes of amyotrophic lateral sclerosis and frontotemporal dementia. The hexanucleotide expansion, formed by GGGGCC (G4C2) repeats, leads to the production of five dipeptide protein repeats (DPRs) via repeat-associated non-AUG translation. Among the five dipeptide repeats, Gly-Arg, Pro-Arg, and Gly-Ala form neuronal inclusions that contain aggregates of the peptides. Several studies have attempted to model DPR-associated toxicity using various repeat lengths, which suggests a unique conformation that is cytotoxic and is independent of the repeat length. However, the structural characteristics of DPR aggregates have yet to be determined. Increasing evidence suggests that soluble species, such as oligomers, are the main cau2024-01-01T00:00:00Z2024 Jan2025-04-22T03:17:46.243Z2025-04-05T20:43:21.729ZS-EPMC108447443829572910.1016/j.jbc.2024.105628