Increased neuronal activity restores circadian functionin Drosophila models of C9orf72-ALS/FTD

Abstract

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 toxic 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 disrupted in a repeat number-, dosage-, 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 restored circadian function under select conditions. These results implicate reduced neuronal activity in C9orf72-ALS/FTD circadian deficits, underscoring the importance of precisely tuned, circuit- and stage-specific interventions. HighlightsO_LIC9orf72 dipeptide and nucleotide repeats disrupt circadian rhythms in Drosophila C_LIO_LICircadian dysfunction with reduced PDF and neurites emerges before neuron loss C_LIO_LIIncreased neuronal activity rescues mild circadian dysfunction C_LIO_LIActivity-based rescue is effective across ages and models when precisely tuned C_LI