FUS Protein Homeostasis in ALS
ALS 中的 FUS 蛋白稳态
基本信息
- 批准号:10550115
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-10-01 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:ALS patientsAddressAffectAgonistAmyotrophic Lateral SclerosisAnimal ModelAttenuatedBioinformaticsCategoriesCell LineCell NucleusCell physiologyCellsCessation of lifeContractsCytoplasmCytoplasmic GranulesDNA BindingDefectDiagnosisDiseaseDrosophila genusEndoplasmic ReticulumEquilibriumFoundationsFunctional disorderFutureGenesGeneticGenetic ModelsHealthHealthcareHydrogelsHyperactivityImpairmentIn VitroInclusion BodiesInterventionKnock-outKnowledgeLiquid substanceMediatingMembrane ProteinsMessenger RNAModelingMolecularMotor NeuronsMutationN-terminalNerve DegenerationNeurodegenerative DisordersNeuronsNonsense-Mediated DecayPathologicPathologyPathway interactionsPharmacologyPhasePhenotypePhysiologicalPlayPost-Translational Protein ProcessingPropertyProtein BiosynthesisProteinsProteomeProteomicsPublishingRNARNA BindingRNA DecayRNA-Binding ProteinsRattusReportingRibonucleoproteinsRoleServicesSpecificityTestingToxic effectTransgenic MiceTransgenic OrganismsTranslationsVeteransamyotrophic lateral sclerosis therapyattenuationbasecare costscopper zinc superoxide dismutasecostdesigndisabilityeffective therapyfamilial amyotrophic lateral sclerosisfused in sarcomahigh riskimprovedin vivoin vivo Modelinduced pluripotent stem cellinhibitorinnovationinsightmRNA DecaymRNA Surveillancemilitary servicemilitary veteranmutantneuron lossneurotoxicitynoveloverexpressionprion-likeprotein TDP-43proteostasissporadic amyotrophic lateral sclerosistau Proteinstherapeutic developmenttranscriptometranscriptomicsunpublished works
项目摘要
Amyotrophic lateral sclerosis (ALS) is a poorly understood neurodegenerative disease with no effective
treatment. ALS is connected with military service and veterans are at a higher risk of developing this debilitating
disease. Mutations in several genes have been discovered to cause a subset of familial ALS, including copper-
zinc superoxide dismutase (SOD1), Fused in Sarcoma (FUS), and TAR DNA-binding protein 43 (TDP-43).
Studying familial ALS using the well-defined genetic models will provide critical insights into the disease
pathology as well as novel targets for future therapeutic development.
This project is focused on the RNA binding protein FUS that has been implicated in both familial and
sporadic ALS. ALS-related mutations in FUS cause a liquid-liquid phase separation (LLPS) of the FUS protein,
forming liquid droplets in vitro. In neurons, mutant FUS accumulates in the cytoplasm, forming ribonucleoprotein
granules and inclusions, eventually leading to neurotoxicity. We recently identified cellular proteins in FUS-
positive inclusions and a bioinformatics analysis revealed two previously unknown pathways affected by mutant
FUS: protein translation and mRNA surveillance. We also demonstrated that ALS FUS mutations indeed
suppressed protein translation and hyper-activated the nonsense-mediated decay (NMD) of mRNAs. Our
overarching hypothesis is that the dysregulation of protein translation and mRNA nonsense-mediated decay
contributes to FUS toxicity and motor neuron dysfunction. Since little is known about how the mutant FUS-
induced dysregulation of protein translation and NMD cause toxicity in neurons, discoveries in this project will fill
this knowledge gap and advance the field significantly.
Three specific aims are designed to test the hypothesis. Aim 1 is to determine what properties of mutant
FUS drive the dysregulation of protein translation and NMD. We will use different domain truncations of FUS to
manipulate LLPS and examine the relationship between LLPS and mutant FUS dysregulation. In addition, we will
manipulate RNA binding of FUS and test whether RNA binding is a significant contributor to mutant FUS
dysfunction. We will also use FUS knockout models to examine whether FUS plays a role in in protein translation
and NMD under physiological conditions. Aim 2 is to determine whether mutant FUS impairs translation of
specific proteins and NMD of specific mRNAs. We will employ specialized proteomic and transcriptomic
approaches to identify changes of nascent protein biosynthesis and mRNA turnover rate as a consequence of
mutant FUS. Differentially altered proteins and mRNAs will be validated in animal models as well as iPSC and
induced motor neurons derived from familial ALS patients. Results from these -omics approaches will be
integrated to determine whether mutant FUS impairs specific molecular and cellular function and pathways. Aim
3 is to examine whether attenuation of NMD hyperactivity can restore protein translation and mitigate FUS
neurotoxicity. We will use genetic and pharmacological approaches to attenuate NMD hyperactivity and
determine whether the intervention can restore the balance and mitigate FUS toxicity in vitro and in vivo models.
The proposed studies are highly innovative, both conceptually and technically. The proposal is based on
a number of novel observations regarding the impact of ALS mutant FUS on protein translation and mRNA
decay. The results from this project are expected to produce new mechanistic insights into FUS ALS, laying a
foundation for future therapeutic development of new ALS treatment(s).
肌萎缩侧索硬化症(ALS)是一种知之甚少、疗效不佳的神经退行性疾病。
治疗。肌萎缩侧索硬化症与服兵役有关,退伍军人患这种疾病的风险更高。
疾病。几个基因的突变已被发现导致家族性ALS的一个子集,包括铜-
锌超氧化物歧化酶(SOD1)、肉瘤融合蛋白(FUS)和TAR DNA结合蛋白43(TDP-43)。
利用明确定义的遗传模型研究家族性肌萎缩侧索硬化症将提供对该疾病的关键见解
病理学以及未来治疗发展的新靶点。
这个项目的重点是rna结合蛋白fus,它与家族性和
散发性肌萎缩侧索硬化症。与肌萎缩侧索硬化症相关的FUS突变导致FUS蛋白的液-液分离(LLP),
在体外形成液滴。在神经元中,突变的fus聚集在细胞质中,形成核糖核蛋白。
颗粒和包裹体,最终导致神经毒性。我们最近在FUS中发现了细胞蛋白-
阳性包涵体和生物信息学分析揭示了两条以前未知的受突变影响的途径
FUS:蛋白质翻译和信使核糖核酸监测。我们还证明了肌萎缩侧索硬化症FUS突变确实
抑制蛋白质翻译并过度激活无意义介导的mRNAs衰变(NMD)。我们的
最重要的假说是蛋白质翻译的失调和信使核糖核酸无义介导的衰变
会导致FUS毒性和运动神经元功能障碍。因为几乎不知道突变体是如何-
诱导的蛋白质翻译失调和NMD导致神经元毒性,该项目的发现将填补
这一知识鸿沟大大推进了该领域的发展。
为了检验这一假说,我们设计了三个具体目标。目标1是确定突变体的哪些特性
FUS导致蛋白质翻译失调和NMD。我们将使用FU的不同域截断来
操纵LLPs并检查LLPs和突变的FU失调之间的关系。此外,我们还将
操纵FU的RNA结合,并测试RNA结合是否对突变的FUS有显著影响
功能障碍。我们还将使用fus基因敲除模型来检验fus在蛋白质翻译中是否起作用。
和生理条件下的NMD。目的2是确定突变的FUS是否损害翻译
特定蛋白和特定mRNAs的NMD。我们将使用专门的蛋白质组和转录组
确定新生儿蛋白质生物合成和信使核糖核酸周转率变化的方法
变种人Fus。差异改变的蛋白质和mRNAs将在动物模型以及IPSC和
家族性肌萎缩侧索硬化症患者来源的诱导运动神经元。这些组学方法的结果将是
整合以确定突变的FUS是否损害特定的分子和细胞功能和途径。目标
3是检查NMD过度活动的减弱是否可以恢复蛋白质翻译和减轻FUS
神经毒性。我们将使用遗传和药物方法来减轻NMD过度活动和
在体外和体内模型中,确定干预是否能够恢复平衡并减轻FUS的毒性。
拟议的研究在概念和技术上都具有很高的创新性。该提案的基础是
肌萎缩侧索硬化症突变体fus对蛋白质翻译和信使核糖核酸影响的若干新观察
腐烂。该项目的结果有望对FUS ALS产生新的机械学见解,为
为今后肌萎缩侧索硬化症治疗的新发展奠定基础(S)。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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{{ truncateString('Haining Zhu', 18)}}的其他基金
RNA Surveillance and Protein Translation in FTD
FTD 中的 RNA 监测和蛋白质翻译
- 批准号:
10687846 - 财政年份:2021
- 资助金额:
-- - 项目类别:
RNA Surveillance and Protein Translation in FTD
FTD 中的 RNA 监测和蛋白质翻译
- 批准号:
10449486 - 财政年份:2021
- 资助金额:
-- - 项目类别:
RNA Surveillance and Protein Translation in FTD
FTD 中的 RNA 监测和蛋白质翻译
- 批准号:
10455737 - 财政年份:2021
- 资助金额:
-- - 项目类别:
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