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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