Increased neuronal activity restores circadian function in Drosophila models of C9orf72-ALS/FTD.

Circadian rhythm disruptions are common across neurodegenerative diseases, but their link to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) remains unclear. The C9orf72 hexanucleotide repeat expansion is the most prevalent genetic cause of ALS/FTD. Here, we used Drosophila models expressing pathogenic arginine-rich dipeptides (PR or GR) or GGGGCC hexanucleotide repeats to investigate circadian deficits in C9orf72-ALS/FTD. We found that circadian rhythmicity and period length were altered in a repeat number-, dosage-, expression pattern-, and age-dependent manner. Additionally, we observed lower levels of the neuropeptide PDF, a key regulator of free-running circadian rhythms, as well as decreased projection complexity and reduced neuronal activity in PDF-expressing neurons. Importantly, increases in neuronal activity significantly rescued mild circadian dysfunction across ages and across PR, GR, and GGGGCC repeat models when appropriately tuned. These results implicate reduced neuronal activity in C9orf72-ALS/FTD circadian deficits, underscoring the importance of calibrated, and stage-specific interventions.