A study shows that the expansion of GGGGCC (G4C2) hexanucleotide repeats in the C9orf72 gene, the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), causes neuronal damage through toxic proteins, not RNA.[5][6] These disorders form the ALS/FTD continuum with shared clinical, pathological, and genetic features.[5] Researchers Jiang et al. used adeno-associated virus constructs to introduce a CUG codon to CCG mutation in mice, disrupting the synthesis of toxic dipeptide repeat (DPR) proteins but preserving the expression of the repeat RNA.[6] The mice showed improved behavioral deficits, reduced neuroinflammation, fewer protein aggregates, and higher neuronal survival.[6] Using CRISPR base editing, they changed CUG to CCG in induced pluripotent stem cells (iPSC) from C9orf72 patients, which significantly reduced DPR production in derived neurons.[6] These editing neurons partially or fully restored transcript changes, STING activation, loss of neurite density, mislocalization of nuclear pore proteins, and survival deficits.[6] Despite persistent RNA foci, complex phenotype rescues in mouse and iPSC models confirm that DPRs are major drivers of the pathogenesis of C9orf72-related ALS and FTD.[6] The results suggest the potential of therapeutic strategies targeting DPR synthesis instead of reducing RNA with repeats.[6]