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Study on hnRNPA1 Pathobiology in ALS

hnRNPA1在ALS中的病理学研究

基本信息

批准号：
10188709
负责人：
xugang xia
金额：
$ 31.79万
依托单位：
FLORIDA INTERNATIONAL 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：
2020-06-11 至 2022-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10188709
关键词：
ALS patients Affinity Alleles Aminobutyric Acids Amyotrophic Lateral Sclerosis Animal Model Animals Binding Biological Assay Biological Markers Biological Models 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 Pattern Phenotype Physiological Play Point Mutation Protein Import Proteins RNA RNA Processing Rattus Research Ribonucleoproteins Role Signal Pathway Therapeutic Effect Transgenic Animals Transgenic Organisms Untranslated Regions 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 preservation 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（由申请人提供）：最近在多个患有肌萎缩侧索硬化症（ALS）的家族中发现了 hnRNPA1 突变。已知 HnRNPA1 可以调节 RNA 加工并与不同细胞功能相关的蛋白质相互作用，但 hnRNPA1 突变如何导致疾病尚不清楚。了解 hnRNPA1 发病机制的关键一步是在系统和分子水平上确定致病性突变对 hnRNPA1 功能的影响。 HnRNPA1、TDP-43和FUS属于核糖核蛋白家族，它们的突变均与ALS相关。三种核糖核蛋白在疾病特征上表现出相似性：1）疾病表现出常染色体显性遗传特征； 2）该病以蛋白质病和线粒体损伤为突出； 3）野生型和突变型在动物模型中过度表达时都会引起疾病。即使在 ALS 中发现 TDP-43 突变七年后，TDP-43 突变如何导致这种疾病仍然难以捉摸。我们的初步研究表明，hnRNPA1 表达不足和过量都会分别导致 hnRNPA1 敲低和转基因大鼠的神经毒性，这表明 hnRNPA1 必须受到严格调控才能维持其正常功能。为了揭示致病性突变对 hnRNPA1 的影响，我们创建了 hnRNPA1 敲入大鼠，其中引入了单一致病性突变。敲入大鼠与野生型同窝大鼠的不同之处在于所检查的单个核苷酸。在敲入大鼠中检测到的任何表型必定是致病性突变的结果。通过前所未有的大鼠模型，我们将研究致病性突变如何在系统和分子水平上影响 hnRNPA1 功能，揭示 hnRNPA1 突变导致 ALS 神经退行性变的机制。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Increased Ubqln2 expression causes neuron death in transgenic rats.

DOI：
10.1111/jnc.13748
发表时间：
2016-10
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Huang B;Wu Q;Zhou H;Huang C;Xia XG
通讯作者：
Xia XG

Detergent-insoluble inclusion constitutes the first pathology in PFN1 transgenic rats.

DOI：
10.1111/jnc.15139
发表时间：
2021-05
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Yuan G;Cui S;Chen X;Song H;Huang C;Tong J;Yuan Z;Yu L;Xiong X;Zhao J;Huang B;Wu Q;Zhou Y;Chen G;Zhou H;Xia XG
通讯作者：
Xia XG

Increase in hnRNPA1 Expression Suffices to Kill Motor Neurons in Transgenic Rats.