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聚引起的。 从而促进细胞凋亡。P97 AAA ATPase(也称为VCP、CDC48、TER ATPase)在 多个生物过程，针对两个主要降解系统的蛋白质，蛋白酶体和 自噬机器。P97在蛋白酶体和自噬降解中的关键作用强调了它 P97异常调节在蛋白质错误折叠、聚集和加工中的重要性和支持性 错误，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遗传性(FTD)和一种称为 包涵体肌病伴骨Paget病合并ALS，一种运动神经元病，也称为Lou 格里克病。突变来源可能是遗传的、环境的、自发的或与年龄有关的。的目标是 这个项目是为了确定关键的致病机制，这些机制将被用来开发精确的治疗方法来纠正 P97疾病突变所致的缺陷，不损害正常的p97功能。我们的核心假设：第97页 疾病突变体具有异常的构象，进而导致特定的蛋白质相互作用组的改变 包括神经细胞在内的细胞引起致病效应，以检验这一假说并确定关键致病因素 可以作为治疗干预靶点的机制，我们建议比较WT的相互作用组 以及来自患者成纤维细胞的神经细胞和肌肉细胞中p97的疾病突变体，然后使用基因 和生化方法，以确定改变的相互作用对调节p97-ATPase活性的影响 以及在调节疾病表型方面。总体而言，如何开发以突变为目标的新范式 治疗神经退行性疾病--尤其是ATPase蛋白家族的致病突变-- 将会建立起来。