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Cryo-EM Analysis of Ribosomal Defects in C9ORF72-Associated Frontotemporal Dementia and ALS

C9ORF72 相关额颞叶痴呆和 ALS 核糖体缺陷的冷冻电镜分析

基本信息

批准号：
10752450
负责人：
Fen-Biao Gao
金额：
$ 25.13万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10752450
关键词：
Address Affect Alzheimer&apos s Disease American Amyotrophic Lateral Sclerosis Animal Model Anterior Arginine Atrophic Autophagocytosis Autopsy Binding Brain C9ORF72 Cell Nucleus Cell model Cells Clinical Cryoelectron Microscopy DNA Damage DNA Sequence Alteration Data Defect Dementia Development Dipeptides Disease Disinhibition Early Diagnosis Empathy Event Extracellular Space Frontotemporal Dementia G-Quartets Genes Genetic Human Impaired cognition Impairment In Situ In Vitro Induced pluripotent stem cell derived neurons Initiator Codon Introns Language Messenger RNA Methods Mitochondria Molecular Motor Neuron Disease Movement Nerve Degeneration Neurodegenerative Disorders Neurons Neurosciences Research Pathogenicity Pathologic Pathway interactions Patient imaging Patients Peptides Peptidyltransferase Personality Presenile Dementia Production Proteins RNA Records Resolution Ribosomes Role Social Behavior Structure System Temporal Lobe Therapeutic Time Toxic effect Translating Translational Regulation Translational Repression Translations brain tissue frontal lobe frontotemporal lobar dementia amyotrophic lateral sclerosis induced pluripotent stem cell inhibitor language impairment molecular pathology mouse model nanomolar neurotoxicity novel therapeutic intervention nucleocytoplasmic transport polypeptide research and development ribosome profiling stress granule structural biology therapeutic development tool

项目摘要

Abstract Frontotemporal dementia (FTD), caused by atrophy of frontal and/or anterior temporal lobes, is the second most common form of dementia after Alzheimer’s disease. FTD patients often show changes in personality, loss of empathy and disinhibition, or language impairment and movement deficits. The most common genetic cause of FTD is a GGGGCC (G4C2) repeat expansion in the first intron of the C9ORF72 gene. The sense and antisense repeat RNAs are translated into 5 different dipeptide repeat (DPR) proteins that are observed in C9ORF72 patient brain neurons. Among them, poly(GR) and poly(PR) are most toxic but it remains largely unknown which specific molecular and structural mechanisms of action underly their neurotoxicity. In this R21 project, we will examine the high-resolution structural mechanisms of poly(GR) and poly(PR) production by the ribosome, the underlying cis-inhibition of translation by expanded G4C2 repeats and DPR proteins, and translation dysregulation directly in FTD patient neurons. By discovering the molecular mechanisms of C9ORF72-caused FTD and further developing tools for high-resolution structural biology in neurons, our project may open new directions in neuroscience research and therapeutics development of other molecular pathologies underlying dementia.

摘要额颞叶痴呆（FTD）是由额叶和/或前颞叶萎缩引起的，这是仅次于阿尔茨海默氏症的第二种常见的痴呆症。FTD患者通常表现为性格改变，移情和抑制解除的丧失，或语言障碍和运动赤字FTD最常见的遗传原因是GGGGCC（G4 C2）重复扩增， C9 ORF 72基因的第一内含子。正义和反义重复RNA被翻译成5 在C9 ORF 72患者脑神经元中观察到的不同二肽重复（DPR）蛋白。其中，聚（GR）和聚（PR）毒性最大，但其特异性分子和结构作用机制是其神经毒性的基础。在R21项目中，我们将研究高分辨率的聚（GR）和聚（PR）生产的结构机制，核糖体，扩展的G4 C2重复序列和DPR对翻译的潜在顺式抑制直接在FTD患者神经元中的蛋白质和翻译失调。通过发现 C9 ORF 72引起FTD的分子机制和进一步开发高分辨率的工具神经元的结构生物学，我们的项目可能会开辟神经科学研究的新方向，痴呆症潜在的其他分子病理学的治疗学发展。