权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
Mariana Mandi Gandelman
金额：
$ 42.21万
依托单位：
UNIVERSITY OF UTAH
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：
https://reporter.nih.gov/project-details/10668022
关键词：
ALS pathology ALS patients Adenoviruses Affect Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease related dementia Amplifiers Amyotrophic Lateral Sclerosis Antisense Oligonucleotide Therapy Antisense Oligonucleotides Apoptosis Binding Biological Assay C9ORF72 Cell Line Clinical Trials Co-Immunoprecipitations Cytoplasm Data Dementia Development Disease Emotional Family Fibroblasts Financial Hardship Foundations Functional disorder G3BP1 gene Genetic Health Health system In Vitro Inclusion Bodies Individual Investigation Knock-out Knockout Mice Knowledge Lightning Link Maps Modeling Molecular Motor Neurons Mus Mutate Mutation Myopathy Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Injury Neurons Nuclear Matrix Pancreatic ribonuclease Pathogenicity Pathologic Pathology Pathway interactions Patients Pharmacologic Substance Phase Phenotype Physical condensation Population PrP Predisposition Proteins Purkinje Cells RNA RNA Interference RNA Splicing RNA-Binding Proteins Recombinants Risk Role SCA2 protein Site Solubility Stress Study models TDP-43 aggregation Therapeutic Therapeutic Intervention Toxic effect Translating Type 2 Spinocerebellar Ataxia Work familial amyotrophic lateral sclerosis frontotemporal lobar dementia amyotrophic lateral sclerosis improved knock-down mRNA Translation matrin 3 mouse model multisystem proteinopathy nervous system disorder neuron loss neuronal survival neurotoxicity novel overexpression phase I trial polyglutamine precision medicine protein TDP-43 sporadic amyotrophic lateral sclerosis stress granule success superresolution microscopy targeted 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。