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The pathogenic relationship between neuronal activity and C9orf72-linked neurodegeneration

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：
10052760
负责人：
Aaron Raymond Haeusler
金额：
$ 215.98万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10052760
关键词：
ALS patients Acute Age Aging Amyotrophic Lateral Sclerosis Animal Model Appearance Autopsy Bacterial Artificial Chromosomes Behavioral Biochemical Biological Assay C9ORF72 Cell Nucleus Cells Cellular Stress Chronic DNA Sequence Alteration Defect Dipeptides Disease Disease model Epilepsy Etiology Foundations Frontotemporal Dementia Genetic Genetic Transcription Half-Life Human Imaging Techniques In Vitro Intervention Investigation Link Measures Modeling Motor Mus Mutation Nerve Degeneration Neurodegenerative Disorders Neuromuscular Diseases Neurons Neuropathogenesis Nucleoproteins Nucleotides Pathogenesis Pathogenicity Pathologic Pathology Patients Pharmacology Phenotype Physiological Production Proteins RNA Reporting Research Proposals Role Stress Techniques Testing Tissues Toxic effect Transcript Translations Variant Work age related base biological adaptation to stress excitotoxicity frontotemporal lobar dementia-amyotrophic lateral sclerosis gain of function in vivo in vivo Model induced pluripotent stem cell loss of function mouse model multi-electrode arrays nervous system disorder neurophysiology neurotoxic novel novel therapeutic intervention novel therapeutics prevent response serial imaging spatiotemporal transcriptome

项目摘要

Project Summary The nucleotide repeat expansion (NRE) mutation on chromosome 9 open reading frame 72 (C9orf72) has been identified as the most common genetic mutation link to frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). It has become clear that these two diseases exist in a spectrum of neurological and neuromuscular disorders based on overlapping pathological features identified in patients post-mortem tissue, yet the mechanistic cause for neuropathogenesis is unclear. Age-dependent hyper- and/or hypo-excitability has been a well-described feature of ALS and is now being reported in FTD/ALS patients and patient-derived induced pluripotent stem cells (iPSCs) that carry the C9orf72 NRE mutation. Moreover, aberrant neuronal activity increases with age and can contribute to accelerated aging in animal models. Although the neurospecific contribution for loss-of-function of the C9orf72 protein is not well described, two C9orf72 NRE gain-of-function mechanisms, RNA toxicity from the bidirectional transcription of the NRE and/or dipeptide repeat (DPR) toxicity from the non-AUG-dependent translation of the NRE, have been shown to contribute to neurotoxic mechanisms. We recently identified a potential link between aberrant neuronal activity and increased DPR toxicity, where increased excitotoxic stress or repetitive neuronal activation can drive DPR production. However, further investigation is crucial to understand these in vitro observations and to determine if these may contribute to C9orf72 NRE-linked disease pathogenesis in vivo. Therefore, in this research proposal we hypothesize that abnormal activity increase neurophysiological stress that can modify C9orf72 NRE-linked neuropathogenesis and thereby increase the pathological burden in C9orf72 NRE bacterial artificial chromosome (BAC) disease models, which currently lack overt or robust FTD or ALS phenotypes. Additionally, we postulate that aberrant activity will alter the spatiotemporal gain-of-function toxicity. To test these hypotheses, we will utilize a battery of biochemical to cellular longitudinal assays while utilizing C9orf72 NRE human iPSC and in vivo models to test the causal relationship among aberrant neuronal activity and spatiotemporal dynamics of C9orf72 NRE derived RNA and DPRs using novel patient derived neuronal models and then validate these finds in vivo. Ultimately, we anticipate that this work will establish a crucial foundation for understanding the spatiotemporal causal relationship between neurophysiological stress caused by aberrant neuronal activity and C9-RNE-linked pathogenesis in vitro and in vivo, as well as reveal new therapeutic intervention opportunities to treat neurogenerative disorders linked to the C9-NRE mutation.

项目总结