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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

基本信息

批准号：
10034670
负责人：
Jie Jiang
金额：
$ 39万
依托单位：
EMORY 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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10034670
关键词：
Ablation Address Alzheimer&apos s Disease Antisense Oligonucleotides Astrocytes Autopsy Bacterial Artificial Chromosomes Behavioral Biological Assay C9ORF72 Cause of Death Cells Cervical lymph node group Clinical Coculture Techniques Data Dipeptides Disease Frontotemporal Dementia Genes Genetic Human Immune Immune response Immune system Immunization Introns Knockout Mice LoxP-flanked allele Mediating Microglia Modeling Molecular Mus Neuraxis 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 macrophage neuroinflammation neuron loss neurotoxicity protein function synergism tool transcriptome transcriptome sequencing

项目摘要

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.

项目总结/文摘