TDP-43 accumulation is a major pathological hallmark of amyotrophic lateral sclerosis and frontotemporal dementia, including the most common genetic cause, G4C2 hexanucleotide repeat expansion in C9ORF72 (C9ALS/FTD). Solomon et al. report that G4C2-derived dipeptide repeat protein but not G4C2-RNA accumulation causes TDP-43 proteinopathy that triggers onset and progression of disease.
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