Supplement -- The pathogenic relationship between neuronal activity and C9orf72-linked neurodegeneration

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ABSTRACT The nucleotide repeat expansion (NRE) mutation located in the chromosome 9 open reading frame 72 (C9orf72) gene is the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), which exist in a spectrum of neurological and neuromuscular disorders. The C9orf72-NRE mutation leads to several cellular abnormalities, including the accumulation of toxic dipeptide repeats (DPRs), which often appear in clinically affected tissues that degenerate in FTD/ALS. Sleep disorders are common in Alzheimer’s disease (AD) and AD related dementia (ADRD) patients, and accumulating evidence suggests that the relationship between sleep/circadian disruptions and AD/ADRD is bi-directional. While AD/ADRD causes sleep disturbances/circadian disruption, disrupted sleep/circadian rhythms can accelerate AD/ADRD pathologies, and reduced sleep is associated with an increased risk of late-onset dementia. Moreover, animal studies suggest that sleep interventions could reverse cognitive deficits in AD models. Although sleep and circadian disorders are frequently associated with FTD/ALS and have been reported for patients carrying the C9orf72-NRE mutation, it is unknown if sleep manipulations can modify disease progression. Building on our recent in vitro findings linking aberrant neuronal activity to increased dipeptide repeat (DPR) toxicity, the parent award aims to test whether aberrant neuronal activity modifies C9orf72-NRE-linked neurodegeneration using novel patient derived neuronal models and then validate these findings using mouse models. In this supplemental project, we propose to examine the relationship between sleep and FTD pathologies in both Drosophila and mouse models of the C9orf72 NRE mutation. In Aim 1, we will examine the sleep and short- term memory (STM) phenotypes of the Drosophila models and test whether sleep and excitability manipulations can modify C9orf72 NRE behavioral phenotypes and cellular abnormalities. In Aim 2, we will determine the effects of sleep deprivation on FTD-relevant behavioral defects and cellular pathologies in mouse models. We expect that the innovative and synergistic animal model research will establish a critical foundation for advancing our understanding of the bidirectional relationship between sleep and C9-NRE-inked dementia.