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

补充——神经元活动与C9orf72相关神经变性之间的致病关系

基本信息

批准号：
10401973
负责人：
Aaron Raymond Haeusler
金额：
$ 39万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401973
关键词：
Affect Alzheimer&apos s Disease Alzheimer&apos s disease model Alzheimer&apos s disease related dementia Animal Model Animals Anxiety Appearance Arginine Arousal Attention Attenuated Autopsy Award Behavior Behavioral Biological Assay Brain region C9ORF72 Cations Circadian Dysregulation Circadian Rhythms Clinical Cognitive deficits DNA Damage DNA Repair DNA Repeat Expansion DNA Sequence Alteration Defect Dementia Dipeptides Disease Disease Progression Disease model Drosophila genus Eye Foundations Frontotemporal Dementia Generations Genes Genetic Goals Hyperactivity Hypothalamic structure Impaired cognition Impulsivity In Vitro Induced pluripotent stem cell derived neurons Ink Intervention Investigation Link Longevity Marble Mechanical Stimulation Memory Methods Modeling Molecular Monitor Motor Mus Mutation Names Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Neurons Nucleotides Parents Pathogenesis Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmaceutical Preparations Phenotype Process Protocols documentation Reaction Time Reporting Research Risk Short-Term Memory Sleep Sleep Deprivation Sleep Disorders Sleep Wake Cycle Sleep disturbances Speed Testing Therapeutic Tissues Toxic effect Transgenic Mice Untranslated RNA Work behavior measurement behavior test behavioral phenotyping behavioral study biological adaptation to stress cell type cellular pathology circadian comorbidity excitotoxicity executive function experience frontotemporal lobar dementia-amyotrophic lateral sclerosis innovation insight mouse model mutant nervous system disorder neuronal excitability novel object recognition preservation protein TDP-43 proteotoxicity relating to nervous system stressor tissue culture

项目摘要

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.

摘要