Molecular pathways linking frontotemporal dementia and circadian dysfunction

PROJECT SUMMARY Frontotemporal dementia (FTD) is a neurodegenerative disease that belongs to a group of Alzheimer’s disease and related dementias (AD/ADRD) and is one of the most common dementias for people under 60. Our internal circadian clock controls numerous critical biological processes, including sleep-wake cycles. Circadian and sleep disruptions are prevalent among patients with neurodegenerative diseases, including FTD. Evidence suggests that neurodegenerative diseases cause circadian/sleep dysfunction, while circadian/sleep disturbances can accelerate disease progression. However, the molecular and cellular mechanisms linking neurodegenerative diseases to circadian and sleep disruptions are not well understood. We propose to perform an unbiased genome-wide screen in Drosophila to identify candidate molecular pathways underlying the association between FTD and circadian dysfunction. We will focus on the GGGGCC (G4C2) nucleotide repeat expansion (NRE) in C9orf72 (C9), the most common genetic mutation causing FTD and amyotrophic lateral sclerosis, two overlapping diseases on a neurodegenerative spectrum. The C9-NRE mutation leads to the accumulation of highly toxic arginine-rich dipeptide repeats (DPRs). Preliminary data show that expressing G4C2 repeats or DPRs in Drosophila leads to circadian period lengthening and reduced rhythmicity. The circadian deficits occur before clock neuron degeneration, which provides exciting opportunity to discover C9-interacting molecules acting in the early stages of FTD pathogenesis. In Aim 1, we will conduct an unbiased genome-wide screen using a collection of deficiencies (deletions that remove multiple genes), which provides 98.3% coverage of the entire Drosophila genome with only 474 deficiencies. In Aim 2, we will determine the role of the Toll pathway in the C9 pathologies. We discovered the conserved Toll signaling pathway as a modifier of C9-linked circadian phenotypes in our preliminary examination of candidate genes. The Toll pathway has highly conserved roles in innate immunity and is also implicated in circadian regulation. However, whether the Toll pathway plays a role in C9-linked diseases is unknown. Our study will identify novel genetic modifiers of C9-related circadian dysfunction and provide new insights into the links between FTD, circadian rhythms, and innate immunity.