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RNA Surveillance and Protein Translation in FTD

FTD 中的 RNA 监测和蛋白质翻译

基本信息

批准号：
10455737
负责人：
Haining Zhu
金额：
$ 53.85万
依托单位：
UNIVERSITY OF ARIZONA
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：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10455737
关键词：
Acetylation Affect Age Amyotrophic Lateral Sclerosis Animal Model Cell Culture Techniques Cell Nucleus Cell model Cell physiology Clinical Cultured Cells Cytoplasm Disease Disease Progression Etiology Frontotemporal Dementia Functional disorder Future Genetic Impairment In Vitro Label Light Liquid substance Lobe Measures Mediating Membrane Messenger RNA Methods Molecular Mus Mutation Names Nerve Degeneration Neuronal Dysfunction Neurons Nonsense-Mediated Decay Pathogenesis Pathogenicity Pathologic Pathology Pathway Analysis Pathway interactions Patients Phase Play Polyribosomes Post-Translational Protein Processing Process Prosencephalon Proteins Proteomics Protocols documentation Publishing Puromycin RNA RNA Binding Research Ribonucleoproteins Role System Temporal Lobe Testing Tissues Toxic effect Transgenic Mice Translating Translations Work age related base cohort design disease-causing mutation experimental study frontal lobe frontotemporal lobar dementia-amyotrophic lateral sclerosis fused in sarcoma innovation insight interdisciplinary approach mRNA Decay mRNA Surveillance mouse model mutant neuron loss neurotoxicity nonalzheimer dementia novel optogenetics polysome profiling protein aggregation spatiotemporal therapeutic development transcriptome sequencing

项目摘要

Frontotemporal dementia (FTD) is an age-related non-Alzheimer dementia characterized by progressive neuronal loss in the frontotemporal lobes. A subset of FTD is defined by the pathology of protein inclusions positive for Fused in Sarcoma (FUS), thus named FUS-FTD. FTD and amyotrophic lateral sclerosis (ALS) share a wide spectrum of clinical, pathological and genetic features. Pathogenic mutations of FUS cause both ALS and FTD, and FUS proteinopathy is also detected in sporadic diseases. FUS is primarily in the nucleus, but the protein with a disease-causing mutation mislocalizes and accumulates in the cytoplasm. Protein aggregates induced by FUS mutations may sequester other proteins to compromise cellular functions, resulting in impaired neurons. We recently showed that FTD/ALS mutations of FUS suppressed protein translation and hyper-activated the nonsense-mediated decay (NMD) of mRNAs. The hypothesis to be tested in this project is that the dysregulation of protein translation and mRNA surveillance contributes to cortical neuron loss in FUS-FTD. Three specific aims are designed to test the hypothesis using in vitro and animal models as well as FTD patient tissues. Aim 1 is to determine how mRNA NMD and protein translation are perturbed by pathogeneic FUS mutations in FTD mouse models and patient tissues. We will determine whether NMD factors and translation-related proteins are sequestered in FUS inclusions in forebrain neurons in R521G FUS transgenic mice at different ages. We will measure mRNA turnover rates and protein translation efficiency in R521G FUS mice and correlate the perturbations to neuronal dysfunction and FTD disease progression. Moreover, we will examine whether NMD factors and protein translation proteins are sequestered in FTD patient tissues. Aim 2 is to identify specific proteins suppressed by pathogenic FUS in FTD mice. We will apply the puromycin labeling in FTD mice and use the proteomic approach to identify changes in protein translation impacted by mutant FUS in forebrain neurons. In addition, actively translated mRNAs will be identified and quantified in polysome fractions using RNA-Seq. Results from the –omics approaches will be integrated for pathway analysis to reveal whether pathogenic FUS impairs proteins in specific pathways, providing novel insights into the FTD etiology. Aim 3 is to elucidate the significance of RNA binding and post-translational modifications in the dysfunction of pathogenic FUS. We will use a cohort of RNA binding-deficient mutations in an optogenetic Cry2olig-FUS-mCherry system to examine the significance of RNA binding in FUS inclusion formation and dysfunction in cortical neurons. We recently found FUS is acetylated at residues critical to RNA binding, we will test how acetylation-null and -mimicking mutations affect FUS inclusions, NMD and protein translation. In addition, we will also examine whether pathogenic FUS forms RNA-dependent and -independent inclusions that produce different levels of toxicity to neurons. The proposed experiments will thoroughly examine a novel disease mechanism using innovative approaches. Completion of our proposed work will help elucidate molecular mechanisms underlying FUS FTD.

额颞叶痴呆（FTD）是一种以进行性痴呆为特征的与年龄相关的非阿尔茨海默病