Dysregulation of p97/VCP disease mutants in IBM and FTLD-U

IBM 和 FTLD-U 中 p97/VCP 疾病突变体的失调

• 批准号: 9889186
• 负责人: Tsui-Fen Chou
• 金额: $ 51.85万
• 依托单位: CALIFORNIA INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9889186
• 关键词: ALS patients; ATP phosphohydrolase; Affect; Affinity; Alleles; Amino Acids; Amyotrophic Lateral Sclerosis; Animal Model; Apoptosis; Area; Autophagocytosis; Binding; Biochemical; Bioinformatics; Biological Assay; Biological Process; Brain; Cell Death; Cells; Clinical; Data; Defect; Degenerative Disorder; Development; Disease; Disease Marker; Emery-Dreifuss Muscular Dystrophy; Enzymes; Excision; Exhibits; Fibroblasts; Frontotemporal Dementia; Genetic; Genotype; Goals; Golgi Apparatus; Hela Cells; Heterogeneous-Nuclear Ribonucleoproteins; Human; Impairment; Inclusion Bodies; Inclusion Body Myopathy with Early-Onset Paget Disease; Inherited; Integral Membrane Protein; Knock-in Mouse; Knock-out; Lead; Leadership; LoxP-flanked allele; Measures; Mediating; Methodology; Missense Mutation; Mitotic; Modeling; Molecular; Molecular Conformation; Motor Neuron Disease; Motor Neurons; Muscle Cells; Mutate; Mutation; Myopathy; Neurodegenerative Disorders; Neurons; Osteitis Deformans; Pathogenicity; Pathology; Pathway interactions; Patients; Penetrance; Phenotype; Precision therapeutics; Protein Family; Proteins; Proteomics; Public Health; Publishing; Quality Control; Recycling; Regulation; Reporter; Source; Symptoms; System; Testing; Therapeutic Intervention; Ubiquitin; Work; age related; base; caveolin 1; cofactor; design; disease phenotype; experience; experimental study; improved; induced pluripotent stem cell; inhibitor/antagonist; knock-down; macromolecule; mouse model; multicatalytic endopeptidase complex; mutant; nervous system disorder; new therapeutic target; novel therapeutics; overexpression; p97 ATPase; prevent; protein TDP-43; protein misfolding; skills; small molecule inhibitor; stem cells; targeted treatment; valosin-containing protein

Many neurodegenerative diseases are thought to be caused by a buildup of toxic proteins in the brain from or resulting in promotion of apoptosis. p97 AAA ATPase (also known as VCP, CDC48, TER ATPase) functions in multiple biological processes, targeting proteins to 2 major degradation systems, the proteasome and autophagy machinery. The key role of p97 in proteasome and autophagy degradations underscores its importance and supports involvement of p97 dysregulation in protein misfolding, aggregation, and processing errors, eventually resulting in cell death. Single amino acid mutations in p97/VCP cause autosomal dominant human disorders including hereditary frontotemporal dementia hereditary (FTD) and a specific condition called inclusion body myopathy with Paget disease of the bone plus ALS, a motor neuron disease also known as Lou Gehrig's disease. Mutation sources could be genetic, environmental, spontaneous, or age related. The goal of this project is to identify key pathogenic mechanisms that will be used to develop precision therapy to correct the defect due to p97 disease mutations, without damaging normal p97 functions. Our central hypothesis: p97 disease mutants have abnormal conformation, which in turn leads to altered protein interactome that in specific cells including neuronal cells cause pathogenic effect To test this hypothesis and to identify key pathogenic mechanisms that can act as targets for therapeutic intervention, we propose to compare the interactome of WT and disease mutants of p97 in neuronal and muscle cells derived from patient fibroblasts and then use genetic and biochemical approaches to determine the effect of the altered interactors in regulating p97 ATPase activity and in modulating the disease phenotype. Overall, a new paradigm of how to develop mutant-targeted therapeutics for neurodegenerative diseases—especially for causative mutants in the ATPase protein family— will be established.

许多神经退行性疾病被认为是由大脑中有毒蛋白质的积累引起的， 导致促进细胞凋亡。p97 AAA ATP酶（也称为VCP，CDC 48，TER ATP酶）在 多个生物过程，将蛋白质靶向2个主要降解系统，蛋白酶体和 自噬机制p97在蛋白酶体和自噬降解中的关键作用强调了其 重要性和支持p97失调参与蛋白质错误折叠，聚集和加工 最终导致细胞死亡。p97/VCP单氨基酸突变导致常染色体显性遗传 人类疾病，包括遗传性额颞叶痴呆症（FTD）和一种称为 包涵体肌病与佩吉特病的骨加肌萎缩侧索硬化症，运动神经元疾病也称为娄 Gehrig病。突变来源可能是遗传的、环境的、自发的或年龄相关的。的目标 该项目是确定关键的致病机制，将用于开发精确的治疗，以纠正 由于p97疾病突变的缺陷，而不损害正常的p97功能。我们的中心假设：p97 疾病突变体具有异常构象，这反过来又导致改变的蛋白质相互作用组， 为了验证这一假设，并确定关键的致病因素， 机制，可以作为治疗干预的目标，我们建议比较WT的相互作用组 和p97的疾病突变体，然后使用遗传学方法， 和生物化学方法来确定改变的相互作用物在调节p97 ATP酶活性中的作用 以及调节疾病表型。总的来说，一个新的范式，如何开发多目标 神经变性疾病的治疗剂-特别是ATP酶蛋白家族中的致病突变体- 将建立。