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（NDDS），包括肌萎缩性侧索硬化症（ALS），AD/ADRDS和脊髓脑性共济失调2型（SCA2）。 RBP Ataxin-2是ALS的潜在修饰剂，靶向治疗已经在临床试验中。然而，对ALS和痴呆症中ataxin-2的潜在致病机制以及其与其他致病性RBP的相互作用的作用知之甚少。我们发现，核基质RBP Matrin-3与Ataxin-2相互作用，并提出了在ALS/FTD相关神经元中研究该相互作用的建议。 Matrin-3中的突变导致FTD，家族ALS和多系统蛋白质病（MSP）。像TDP-43一样，即使未突变，MATRIN-3蛋白质病也会在ALS/FTD中观察到。在阿尔茨海默氏病（AD）患者神经元中也观察到了基质3的细胞质聚集。我们的初步数据表明，靶向MATR3可能对这些疾病具有治疗性：我们观察到来自ALS和FTD患者C9ORF72和TDP-43突变的成纤维细胞中的Matrin-3过量，通过RNAI降低ATXN2表达来归一化。 FTD/ALS相关的Matrin3-S85C鼠标模型显示了广泛的选择性Purkinje Cell（PC）损失。 PC是SCA2和神经元中受影响的神经元对ataxin-2突变敏感最大的人口。 Matrin-3 S85C小鼠中严重的小脑神经变性表明，Matrin-3和Ataxin-2之间的病理联系可以定义与包括FTD在内的其他NDD相关的神经元死亡途径。我们建议，在疾病的背景下，ataxin-2与Matrin-3的相互作用将有助于病理的发展，而靶向ataxin-2将减轻Matrin-3病理学和神经元死亡。我们计划研究与ataxin-2，Matrin-3和ALS相关的病理学，该病理是源自ataxin-2敲除，ataxin-2膨胀和TDP-43突变的分离的培养神经元中的病理学老鼠。我们将通过表达基质3突变和/或用腺病毒和反义寡核苷酸策略来确定不同RBP的贡献。我们建议研究的病理表型包括基质3水平，定位，溶液的变化，对冷凝物的聚集和对神经元的毒性以及ALS分子读数，包括TDP-43聚集和定位。我们还将调查其他相关蛋白质病生物分子的核武器。在正常，扩展和敲除ataxin-2和突变的TDP-43的背景下分析这些，将告知Ataxin-2，Matrin-3和RBP在SCA2和ALS/FTD中的致病机理中的作用。这项研究将为ALS和FTD患有MATR3突变的ALS和FTD患者以及其他AD/ADRD患者MATRIN-3蛋白质病患者提供直接靶向ATXN2和MATR3的初步概念验证。