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

摘要 位于9号染色体开放阅读框72的核苷酸重复序列扩展(NRE)突变 (C9ORF72)基因是额颞叶痴呆(FTD)和肌萎缩侧索硬化最常见的遗传原因 硬化症(ALS)，存在于一系列神经和神经肌肉疾病中。C9orf72-NRE 突变会导致几种细胞异常，包括有毒二肽重复序列(Dprs)的积累， 它通常出现在FTD/ALS的临床受累组织中。睡眠障碍在以下方面很常见 阿尔茨海默病(AD)和AD相关痴呆(ADRD)患者，越来越多的证据表明 睡眠/昼夜节律紊乱与AD/ADRD之间的关系是双向的。而AD/ADRD 导致睡眠紊乱/昼夜节律紊乱，睡眠紊乱/昼夜节律可加速AD/ADRD 睡眠减少与迟发性痴呆症的风险增加有关。此外，动物 研究表明，睡眠干预可以逆转AD模型的认知缺陷。虽然睡眠和 昼夜节律紊乱经常与FTD/ALS有关，已有报道称携带 C9ORF72-NRE突变，目前尚不清楚睡眠操作是否可以改变疾病的进展。建立在我们的 最近的体外研究发现，神经元活动异常与二肽重复序列(DPR)毒性增加有关， Parent奖旨在测试异常的神经元活动是否会改变C9orf72-NRE相关的神经变性 使用新的患者衍生的神经元模型，然后用小鼠模型验证这些发现。在这 作为补充项目，我们建议检查睡眠和FTD病理之间的关系 果蝇和小鼠的C9orf72 NRE突变模型。在目标1中，我们将检查睡眠和短时- 果蝇模型的术语记忆(STM)表型，并测试睡眠和兴奋性 手法可以改变C9orf72 NRE的行为表型和细胞异常。在目标2中，我们将 确定睡眠剥夺对FTD相关行为缺陷和细胞病理的影响 老鼠模型。我们期待创新和协同的动物模型研究将建立一个关键的 促进我们对睡眠和C9-NRE之间双向关系的理解的基础 痴呆症。

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.