Investigation on Ataxin2 and Matrin3 in neurodegenerative disease
Ataxin2 和 Matrin3 在神经退行性疾病中的研究
基本信息
- 批准号:10668022
- 负责人:
- 金额:$ 42.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:ALS pathologyALS patientsAdenovirusesAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease patientAlzheimer&aposs disease related dementiaAmplifiersAmyotrophic Lateral SclerosisAntisense Oligonucleotide TherapyAntisense OligonucleotidesApoptosisBindingBiological AssayC9ORF72Cell LineClinical TrialsCo-ImmunoprecipitationsCytoplasmDataDementiaDevelopmentDiseaseEmotionalFamilyFibroblastsFinancial HardshipFoundationsFunctional disorderG3BP1 geneGeneticHealthHealth systemIn VitroInclusion BodiesIndividualInvestigationKnock-outKnockout MiceKnowledgeLightningLinkMapsModelingMolecularMotor NeuronsMusMutateMutationMyopathyNatureNerve DegenerationNeurodegenerative DisordersNeuronal InjuryNeuronsNuclear MatrixPancreatic ribonucleasePathogenicityPathologicPathologyPathway interactionsPatientsPharmacologic SubstancePhasePhenotypePhysical condensationPopulationPrPPredispositionProteinsPurkinje CellsRNARNA InterferenceRNA SplicingRNA-Binding ProteinsRecombinantsRiskRoleSCA2 proteinSiteSolubilityStressStudy modelsTDP-43 aggregationTherapeuticTherapeutic InterventionToxic effectTranslatingType 2 Spinocerebellar AtaxiaWorkfamilial amyotrophic lateral sclerosisfrontotemporal lobar dementia amyotrophic lateral sclerosisimprovedknock-downmRNA Translationmatrin 3mouse modelmultisystem proteinopathynervous system disorderneuron lossneuronal survivalneurotoxicitynoveloverexpressionphase I trialpolyglutamineprecision medicineprotein TDP-43sporadic amyotrophic lateral sclerosisstress granulesuccesssuperresolution microscopytargeted treatment
项目摘要
Dysfunction or mutation of RNA binding proteins (RBPs) is associated with a growing number of
neurodegenerative diseases (NDDs), including amyotrophic lateral sclerosis (ALS), AD/ADRDs and spinocerebellar ataxia type 2 (SCA2). The RBP Ataxin-2 is a potent modifier of ALS and targeting therapeutics are already in clinical trials. However, the underlying pathogenic mechanisms of Ataxin-2 in ALS and dementias, and the roles of its interaction with other pathogenic RBPs are poorly understood. We found that the nuclear matrix RBP Matrin-3 interacts with Ataxin-2 and propose to study the interaction functionally in ALS/FTD-relevant neurons. Mutations in Matrin-3 cause FTD, familial ALS and multisystem proteinopathy
(MSP). Like TDP-43, Matrin-3 proteinopathy has been observed in ALS/FTD even when it is not mutated. Cytoplasmic aggregation of Matrin-3 has also been observed in Alzheimer’s disease (AD) patient neurons. Our preliminary data suggest that targeting MATR3 may be therapeutic for these disorders: We observed Matrin-3 overabundance in fibroblasts from ALS and FTD patients with C9ORF72 and TDP-43 mutations, that was normalized by lowering ATXN2 expression by RNAi. The FTD/ALS-relevant Matrin3-S85C mouse model displays extensive selective Purkinje cell (PC) loss. PCs are the neurons affected in SCA2 and the neuronal
population with the greatest susceptibility to Ataxin-2 mutations. The severe cerebellar neurodegeneration in Matrin-3 S85C mice suggests a pathological link between Matrin-3 and Ataxin-2 that could define a neuronal death pathway relevant to other NDDs including FTD. We propose that in the context of disease, Ataxin-2 interaction with Matrin-3 will contribute to the development of pathology, and that targeting Ataxin-2 will mitigate Matrin-3 pathology and neuronal death. We plan to study pathology linked to Ataxin-2, Matrin-3 and ALS in isolated cultured neurons derived from Ataxin-2 knockout, Ataxin-2 expansion and TDP-43 mutation
mice. We will determine the contribution of the different RBPs by expressing Matrin-3 mutations and/or knocking down Ataxin-2 with adenovirus and antisense oligonucleotide strategies already developed. The pathological phenotypes we propose to study include Matrin-3 levels, localization, changes in solubility, aggregation into condensates and toxicity to neurons, as well as ALS molecular readouts including TDP-43 aggregation and localization. We will also investigate the nucleation of other relevant proteinopathy biomolecules into the condensates. Analyzing these in the context of normal, expanded and knockout Ataxin-2 and mutated TDP-43 will inform on the roles of Ataxin-2, Matrin-3 and the interplay of RBPs in the pathogenetic mechanisms in SCA2 and ALS/FTD. This study will provide the initial proof-of-concept for directly targeting ATXN2 and MATR3 in ALS and FTD patients with MATR3 mutations, as well as in other AD/ADRD patients with Matrin-3 proteinopathy.
RNA 结合蛋白 (RBP) 的功能障碍或突变与越来越多的
神经退行性疾病 (NDD),包括肌萎缩侧索硬化症 (ALS)、AD/ADRD 和 2 型脊髓小脑共济失调 (SCA2)。 RBP Ataxin-2 是 ALS 的有效调节剂,靶向治疗药物已进入临床试验。然而,Ataxin-2 在 ALS 和痴呆中的潜在致病机制及其与其他致病性 RBP 相互作用的作用尚不清楚。我们发现核基质 RBP Matrin-3 与 Ataxin-2 相互作用,并建议研究 ALS/FTD 相关神经元中的功能相互作用。 Matrin-3 突变导致 FTD、家族性 ALS 和多系统蛋白病
(MSP)。与 TDP-43 一样,Matrin-3 蛋白病已在 ALS/FTD 中观察到,即使它没有突变。在阿尔茨海默病 (AD) 患者神经元中也观察到了 Matrin-3 的细胞质聚集。我们的初步数据表明,靶向 MATR3 可能对这些疾病有治疗作用:我们观察到,来自具有 C9ORF72 和 TDP-43 突变的 ALS 和 FTD 患者的成纤维细胞中 Matrin-3 过量,通过 RNAi 降低 ATXN2 表达使这种现象正常化。 FTD/ALS 相关的 Matrin3-S85C 小鼠模型显示出广泛的选择性浦肯野细胞 (PC) 损失。 PC 是 SCA2 中受影响的神经元,而神经元
对 Ataxin-2 突变最敏感的人群。 Matrin-3 S85C 小鼠的严重小脑神经变性表明 Matrin-3 和 Ataxin-2 之间存在病理联系,可以定义与其他 NDD(包括 FTD)相关的神经元死亡途径。我们认为,在疾病背景下,Ataxin-2 与 Matrin-3 的相互作用将有助于病理学的发展,而靶向 Ataxin-2 将减轻 Matrin-3 病理学和神经元死亡。我们计划在 Ataxin-2 敲除、Ataxin-2 扩增和 TDP-43 突变衍生的分离培养神经元中研究与 Ataxin-2、Matrin-3 和 ALS 相关的病理学
老鼠。我们将通过表达Matrin-3突变和/或用腺病毒和已经开发的反义寡核苷酸策略敲低Ataxin-2来确定不同RBP的贡献。我们建议研究的病理表型包括 Matrin-3 水平、定位、溶解度变化、聚集成凝聚物和对神经元的毒性,以及 ALS 分子读数,包括 TDP-43 聚集和定位。我们还将研究其他相关蛋白质病生物分子在冷凝物中的成核。在正常、扩增和敲除的 Ataxin-2 和突变的 TDP-43 的背景下对这些进行分析,将有助于了解 Ataxin-2、Matrin-3 的作用以及 RBP 在 SCA2 和 ALS/FTD 发病机制中的相互作用。这项研究将为在患有 MATR3 突变的 ALS 和 FTD 患者以及其他患有 Matrin-3 蛋白病的 AD/ADRD 患者中直接靶向 ATXN2 和 MATR3 提供初步概念验证。
项目成果
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