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
项目成果
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