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

基本信息

批准号：
10403447
负责人：
Tsui-Fen Chou
金额：
$ 50.39万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10403447
关键词：
ALS pathology 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 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 disease phenotype experience experimental study improved induced pluripotent stem cell inhibitor 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 rational design skills small molecule inhibitor stem cells targeted treatment valosin-containing protein

项目摘要

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.

人们认为许多神经退行性疾病是由大脑中有毒蛋白的积聚引起的导致促进凋亡。 p97 AAA ATPase（也称为VCP，CDC48，TER ATPase）在多个生物学过程，将蛋白质靶向2个主要降解系统，蛋白酶体和自噬机械。 p97在蛋白酶体和自噬降解中的关键作用强调了其重要性并支持P97失调参与蛋白质错误折叠，聚集和处理错误，最终导致细胞死亡。 p97/vcp中的单个氨基酸突变引起常染色体显性人类疾病，包括遗传性额颞痴呆遗传（FTD）和一种特定病名包容体肌病患有骨头疾病的骨骼疾病加ALS，一种运动神经元疾病，也称为lou 格里格氏病。突变来源可能是遗传，环境，赞助或与年龄有关的。目标该项目是确定将用于开发精确疗法以纠正精确疗法的关键致病机制由于p97疾病突变引起的缺陷，而不会损害正常的p97功能。我们的中心假设：p97 疾病突变体具有异常构象，进而导致蛋白质相互作用的改变，在特定中包括神经元细胞在内的细胞会引起致病作用来检验该假设并鉴定关键的致病性我们建议可以作为治疗干预的靶标的机制，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元和肌肉细胞中p97的疾病突变体，然后使用遗传和生化方法以确定变化相互作用者在调节p97 ATPase活性中的影响并调节疾病表型。总体而言，如何开发靶向突变体的新范式神经退行性疾病的疗法，尤其是针对ATPase蛋白家族中的致病突变体的治疗剂 - 将建立。

项目成果

期刊论文数量（15）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Adaptor-Specific Antibody Fragment Inhibitors for the Intracellular Modulation of p97 (VCP) Protein-Protein Interactions.

DOI：
10.1021/jacs.2c03665
发表时间：
2022-07-27
期刊：
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY
影响因子：
15
作者：
Jiang, Ziwen;Kuo, Yu-Hsuan;Zhong, Mengqi;Zhang, Jianchao;Zhou, Xin X.;Xing, Lijuan;Wells, James A.;Wang, Yanzhuang;Arkin, Michelle R.
通讯作者：
Arkin, Michelle R.

Structural and Functional Analysis of Disease-Linked p97 ATPase Mutant Complexes.

DOI：
10.3390/ijms22158079
发表时间：
2021-07-28
期刊：
International journal of molecular sciences
影响因子：
5.6
作者：
Nandi P;Li S;Columbres RCA;Wang F;Williams DR;Poh YP;Chou TF;Chiu PL
通讯作者：
Chiu PL

GRASP depletion-mediated Golgi fragmentation impairs glycosaminoglycan synthesis, sulfation, and secretion.

DOI：
10.1007/s00018-022-04223-3
发表时间：
2022-03-21
期刊：
Cellular and molecular life sciences : CMLS
影响因子：
0
作者：
通讯作者：

Evaluation of artificial signal peptides for secretion of two lysosomal enzymes in CHO cells.

DOI：
10.1042/bcj20210015
发表时间：
2021-06-25
期刊：
BIOCHEMICAL JOURNAL
影响因子：
4.1
作者：
Cheng, Kai-Wen;Wang, Feng;Lopez, George A.;Singamsetty, Srikanth;Wood, Jill;Dickson, Patricia, I;Chou, Tsui-Fen
通讯作者：
Chou, Tsui-Fen

Conserved L464 in p97 D1-D2 linker is critical for p97 cofactor regulated ATPase activity.

DOI：
10.1042/bcj20210288
发表时间：
2021-09-17
期刊：
BIOCHEMICAL JOURNAL
影响因子：
4.1
作者：
Zhang, Xiaoyi;Gui, Lin;Li, Shan;Nandi, Purbasha;Columbres, Rod Carlo;Wong, Daniel E.;Moen, Derek R.;Lin, Henry J.;Chiu, Po-Lin;Chou, Tsui-Fen
通讯作者：
Chou, Tsui-Fen