Cell-type-specific toxicity of C9orf72 repeat expansions in FTD and ALS

FTD 和 ALS 中 C9orf72 重复扩增的细胞类型特异性毒性

• 批准号: 10621887
• 负责人: Jie Jiang
• 金额: $ 39万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621887
• 关键词: Ablation; Address; Alzheimer' s Disease; Antisense Oligonucleotides; Astrocytes; Autopsy; Bacterial Artificial Chromosomes; Behavioral; Biological Assay; C9ORF72; Cause of Death; Cells; Central Nervous System; Cervical lymph node group; Clinical; Coculture Techniques; Data; Dipeptides; Disease; Frontotemporal Dementia; Genes; Genetic; Genetic Transcription; Human; Immune; Immune response; Immune system; Immunologic Stimulation; Introns; Knockout Mice; LoxP-flanked allele; Macrophage; Mediating; Microglia; Modeling; Molecular; Mus; Neurodegenerative Disorders; Neurons; Oligodendroglia; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Play; Production; Proteins; RNA; RNA-Binding Proteins; Role; Sampling; Signal Transduction; Site; Splenomegaly; Synapses; Testing; Therapeutic Intervention; Toxic effect; Transgenic Mice; Translations; Untranslated RNA; Vertebral column; Work; age related; cell type; frontotemporal lobar dementia amyotrophic lateral sclerosis; gain of function; genome-wide; loss of function; neuroinflammation; neuron loss; neurotoxicity; protein function; synergism; tool; transcriptome; transcriptome sequencing

PROJECT SUMMARY/ABSTRACT Expanded GGGGCC hexanucleotide repeats in the C9orf72 gene were recently identified as the most common genetic cause of Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS), two neurodegenerative disorders with clinical, pathological and genetic overlaps. Proposed disease mechanisms include loss of C9orf72 protein function and gain of toxicity from the bidirectionally transcribed sense or antisense repeat-containing RNAs, mediated by sequestration of RNA binding proteins into RNA foci or by production of at least five different aberrant dipeptide repeat (DPR) proteins [GA, GP, GR, PR, and PA] from the intronic sequence through a nonconventional translation mechanism called repeat-associated non-AUG- dependent (RAN) translation. Several studies demonstrated that gain of toxicity from C9orf72 repeat containing RNAs plays a central role in disease pathogenesis. It is yet unknown which specific cell types in the central nervous system is responsible for the disease pathogenesis from gain of toxicity. C9orf72 loss of function alone is insufficient to cause FTD/ALS in mice, but our preliminary data showed it exacerbates diseases together with gain of toxicity. C9orf72 plays an important role in the immune cells as C9orf72 null mice develop splenomegaly and enlarged cervical lymph nodes. However, the function of C9orf72 in microglia and its contribution to FTD/ALS is not determined. In this proposal, will determine 1) molecular pathways altered by C9orf72 loss of function in microglia using genome-wide RNA sequencing and whether such changes in microglia will lead to neuronal toxicity (Aim 1); 2) Whether C9orf72 loss of function in microglia contributes to FTD/ALS pathogenesis caused by gain of toxicity from the repeat containing RNAs in mice (Aim 2); and 3) cell-type-specific toxicity from C9orf72 repeat containing RNAs (Aim 3). If successful, the proposed study will further help us understand the disease mechanisms of C9orf72 repeat expansions in FTD and ALS and identify potential therapeutic interventions.

项目摘要/摘要 C9ORF72基因中扩展的GGGGCC六核苷酸重复序列最近被确定为最多 额颞痴呆（FTD）和肌萎缩性侧面硬化症（ALS）的常见遗传原因，两个 具有临床，病理和遗传重叠的神经退行性疾病。提出的疾病机制 包括C9orf72蛋白功能的丧失以及从双向转录的感觉或 反义重复的RNA，通过将RNA结合蛋白隔离为RNA灶或通过 从至少产生五个不同异常的二肽重复（DPR）蛋白[GA，GP，GR，PR和PA] 通过非惯例翻译机制的内含子序列称为重复相关的非aug- 依赖（ran）翻译。几项研究表明，含有C9orf72重复毒性的毒性获得 RNA在疾病发病机理中起着核心作用。尚不清楚中央中哪种特定细胞类型 神经系统负责毒性获得的疾病发病机理。 C9ORF72功能丧失 仅凭小鼠不足以引起FTD/ALS，但我们的初步数据表明它加剧了疾病 加上毒性。随着C9ORF72无效小鼠的发展，C9ORF72在免疫细胞中起重要作用 脾肿大和宫颈淋巴结肿大。但是，C9orf72在小胶质细胞及其的功能 未确定对FTD/ALS的贡献。在此提案中，将确定1）分子途径已改变 C9ORF72使用全基因组RNA测序在小胶质细胞中的功能丧失，以及这种此类在 小胶质细胞将导致神经元毒性（AIM 1）； 2）C9ORF72小胶质细胞中功能丧失是否有助于 FTD/ALS发病机理是由小鼠重复含有RNA的毒性获得引起的（AIM 2）； 3） C9orf72重复含有RNA的细胞类型特异性毒性（AIM 3）。如果成功，拟议的研究将 进一步帮助我们了解FTD和ALS的C9orf72重复扩张的疾病机制以及 确定潜在的治疗干预措施。