Study on hnRNPA1 Pathobiology in ALS

hnRNPA1在ALS中的病理学研究

基本信息

批准号：
9435362
负责人：
xugang xia
金额：
$ 31.48万
依托单位：
UNIVERSITY OF CENTRAL FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9435362
关键词：
Affinity Alleles Aminobutyric Acids Amyotrophic Lateral Sclerosis Animal Model Animals Binding Biological Assay Biological Markers Biological Models Biological Preservation Biological Process Cell physiology Clinical Disease Disease Progression Electron Transport Endoplasmic Reticulum Exhibits Family Genes Genetic Genetic Engineering Genomics Impairment Knock-in Knock-out Link Longevity Measures Metabolism Mitochondria Mitochondrial Proteins Modeling Molecular Monitor Morphology Mutate Mutation Nerve Degeneration Nucleosides Nucleotides Pathogenesis Pathogenicity Pathway interactions Patients Pattern Phenotype Physiological Play Point Mutation Protein Import Proteins RNA RNA Processing Rattus Research Ribonucleoproteins Role Signal Pathway Therapeutic Effect Transgenic Animals Transgenic Organisms autosomal dominant trait disease-causing mutation egg functional loss gain of function gamma-Aminobutyric Acid improved knock-down knockout animal mitochondrial dysfunction mutant neuropathology neurotoxicity novel overexpression protein TDP-43 public health relevance superoxide dismutase 1

项目摘要

DESCRIPTION (provided by applicant): Mutations in hnRNPA1 are recently found in multiple families with amyotrophic lateral sclerosis (ALS). HnRNPA1 is known to regulate RNA processing and to interact with proteins related to varying cellular functions, but how hnRNPA1 mutation causes disease is not known. A critical step towards understanding hnRNPA1 pathogenesis is determining the effect of pathogenic mutation on hnRNPA1 function at both systematic and molecular levels. HnRNPA1, TDP-43 and FUS belong to ribonucleoprotein family and their mutations are all associated with ALS. The three ribonucleoproteins exhibit similarity in disease features: 1) the disease shows an autosomal dominant trait; 2) proteinopathy and mitochondrial impairment is prominent in the disease; and 3) both wildtype and mutant forms cause diseases when overexpressed in animal models. Even seven years after the discovery of TDP-43 mutation in ALS, how TDP-43 mutation causes the disease remains elusive. Our preliminary studies show that both deficiency and excess in hnRNPA1 expression causes neurotoxicity respectively in hnRNPA1 knockdown and transgenic rats, suggesting that hnRNPA1 must be tightly regulated to maintain its normal function. To unravel the effect of pathogenic mutation on hnRNPA1, we created hnRNPA1 knockin rats in which a single pathogenic mutation is introduced. The knockin rats differ from their wildtype littermates in a single nucleotide examined. Any phenotypes detected in the knockin rats must result from the pathogenic mutation. With unprecedented rat models, we will examine how pathogenic mutation impacts hnRNPA1 function at both the systematic and molecular levels, revealing the mechanism by which hnRNPA1 mutation causes neurodegeneration in ALS.

描述（由适用提供）：HNRNPA1中的突变最近在肌萎缩性侧索硬化症（ALS）的多个家族中发现。已知HNRNPA1可以调节RNA处理并与与细胞功能不同的蛋白质相互作用，但是HNRNPA1突变如何引起疾病。了解HNRNPA1发病机理的关键步骤是确定致病性突变对系统和分子水平上HNRNPA1功能的影响。 HNRNPA1，TDP-43和FUS属于核糖核蛋白家族及其突变都与ALS相关。三种核糖核蛋白在疾病特征中暴露了相似性：1）疾病表现出常染色体显性特征； 2）蛋白质病和线粒体损伤在疾病中很明显； 3）在动物模型中过表达时，野生型和突变形式会引起疾病。甚至在ALS中发现TDP-43突变的七年后，TDP-43突变如何引起该疾病仍然难以捉摸。我们的初步研究表明，HNRNPA1敲低和转基因大鼠的缺乏症和超过HNRNPA1表达都会引起神经毒性，这表明必须严格调节HNRNPA1以维持其正常功能。为了揭示致病突变对HNRNPA1的影响，我们创建了HNRNPA1敲击蛋白大鼠，其中引入了单个致病性突变。在检查的单个核丁物中，敲击大鼠与其野生型同窝窝不同。在敲击大鼠中检测到的任何表型都必须由致病性突变引起。使用前所未有的大鼠模型，我们将研究致病突变如何在系统和分子水平上影响HNRNPA1功能，从而揭示HNRNPA1突变导致ALS神经变性的机制。