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Genetic analysis of UBQLN2-associated neurodegeneration in frontotemporal dementia

额颞叶痴呆中UBQLN2相关神经变性的遗传分析

基本信息

批准号：
10157746
负责人：
Randal Scot Tibbetts
金额：
$ 170万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10157746
关键词：
Address Aging Alleles Alzheimer&apos s disease related dementia Amyotrophic Lateral Sclerosis Apoptosis Applications Grants Attenuated Autopsy Axonal Transport Binding Binding Proteins Biochemical Cell Culture Techniques Cell Line Characteristics Chromosome Mapping Chromosomes Clinical Colon Carcinoma Cytology Defect Dementia Dementia With Amyotrophic Lateral Sclerosis Dependence Development Disease Disease Pathway Dissection Dose Drosophila genus Drosophila melanogaster Enhancers Exhibits Eye Family Frontotemporal Dementia Functional disorder Future Gene Mutation Genes Genetic Genetic Screening Genetic study Goals Heat Stress Disorders Histopathology Human Lead Link Longevity Mammalian Cell Maps Mediating Missense Mutation Modeling Molecular Chaperones Motor Motor Neurons Mutation Natural Immunity Nerve Degeneration Neurodegenerative Disorders Neuromuscular Junction Neurons Neuropathogenesis Orphan Parkinson Disease Pathogenesis Pathologic Pathway interactions Patients Phenotype Photoreceptors Pluripotent Stem Cells Process Production Proline Property Proteins Proteomics Stress System Testing Tissues Toxic effect UBQLN1 gene Ubiquitin Up-Regulation axon guidance cell type drug development fly frontotemporal lobar dementia-amyotrophic lateral sclerosis genetic analysis induced pluripotent stem cell insight interest mutant mutational status neuron apoptosis neuronal survival novel protein aggregation protein degradation protein folding protein function proteostasis proteotoxicity receptor stem cells trafficking transcriptomics ubiquilin

项目摘要

Project summary The overarching goal of this study is to use complementary Drosophila and inducible pluripotent stem cells (iPSC)-derived neuronal models to understand how mutations in the Ubiquilin 2 (UBQLN2) gene cause amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). UBQLN2 and closely related UBQLN1 belong to a family of eukaryotic ubiquitin (Ub)-binding proteins that function, in part, as chaperones for proteins that are destined for proteasomal degradation. Missense mutations within a unique, functionally orphan proline-repeat region (PRR) of UBQLN2 cause X-linked, forms of ALS/FTD, with some patients exhibiting a pure dementia onset. In addition, ubiquilin histopathology, comprised of dense aggregates of UBQLN2 and UBQLN1 are observed in most instances of ALS/FTD regardless of UBQLN2 mutation status. To address pathomechanisms of UBQLN2-associated FTD we exploited the upstream activating sequence (UAS)/GAL4 system to generate isogenic Drosophila strains expressing wild-type (WT) and ALS mutant forms of UBQLN2 in different tissues and cell types. We found that UBQLN2ALS mutants elicited dose-dependent phenotypes— including eye degeneration, motor defects, and lifespan shortening—that were more severe than phenotypes caused by equivalent expression of UBQLN2WT. UBQLN2ALSmutants, but not UBQLN2WT, formed intraneuronal aggregates characteristic of ubiquilin inclusions found in ALS/FTD patients. Unbiased genetic screens identified more than 30 genetic intervals that either reduced or enhanced UBQLN2ALS mutant toxicity. Gene mapping studies suggest that endolysosomal pathways are centrally involved in UBQLN2ALS-mediated neurodegeneration and point toward axon guidance genes and neuronal dependence receptors as potentially novel disease modifiers. In this R01 grant proposal we will continue genetic studies of UBQLN2-mediated neurodegeneration in Drosophila, focusing on endolysosomal trafficking and axon guidance as lead pathways for discovery efforts. Modifier pathways identified in Drosophila will, in turn, inform studies of iPSC-derived motor neurons (iMNs) expressing endogenous UBQLN2ALS alleles. The specific objectives of Aim 1 are to: (a) investigate the Rab5 gene and endolysosomal defects in UBQLN2ALS flies; (b) investigate the contributions of the Unc-5 axon guidance pathway to UBQLN2-mediated neurodegeneration; and (c) map and validate of UBQLN2ALS modifier genes in Drosophila. The specific objectives of Aim 2 are to: (a) establish functional defects in UBQLN2ALS iMNs; (b) carry out proteomic analysis of UBQLN2ALS iMNs; and (c) evaluate genes emerging from Drosophila screens in Aim 1 as genetic modifiers of UBQLN2ALS toxicity in iMNs. The combined genetic, cellular, and biochemical studies using Drosophila and mammalian iMN models will provide important new insights into UBQLN2-associated neurodegeneration in ALS/FTD. In addition, pathways identified in our study are likely to overlap with and inform toxicity pathways instigated by other aggregation-prone, ALS/FTD- associated genes.

项目总结