Identification of novel and disease-related VCP/p97 binding partners and effects of disease-causing VCP/p97 mutations on protein interactions and protein quality control systems in Dictyostelium and mouse

鉴定新型且与疾病相关的 VCP/p97 结合伴侣以及致病 VCP/p97 突变对盘基网柄菌和小鼠蛋白质相互作用和蛋白质质量控​​制系统的影响

• 批准号: 149382352
• 负责人: Professor Dr. Christoph S. Clemen
• 金额: --
• 依托单位: Institut für Luft- und Raumfahrtmedizin
• 依托单位国家: 德国
• 项目类别: Research Units
• 财政年份: 2009
• 资助国家: 德国
• 起止时间: 2008-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/149382352?language=en
• 关键词: Identification; novel; disease; related; VCP

Mutations of the human VCP/p97 gene cause autosomal dominant "Inclusion Body Myopathy with early-onset Paget disease of bone and Frontotemporal Dementia" (IBMPFD) and an "amyotrophic lateral sclerosis" (ALS) variant. In the first funding period, we generated and characterized a series of VCP/p97 mutant Dictyostelium strains, characterized a VCP/p97 haploinsufficient mouse model and identified and characterized novel and disease-relevant VCP/p97 binding partners. In the proposed work program for the second funding period, we will extend our studies on VCP/p97 with particular emphasis on the molecular basis of IBMPFD, employing a broad spectrum of experimental procedures ranging from biochemical and molecular biology experiments, cell biological assays using mammalian and Dictyostelium cells to mouse models. We will identify further novel VCP/p97 binding partners, explore the molecular interactions within VCP/p97 protein complexes and analyze expression changes in autophagy components. We will elucidate functional consequences of R155C mutant VCP/p97 in Dictyostelium strains with respect to proteasomal activity, autophagy flux, and the composition of protein aggregates. Corresponding experiments as well as a detailed characterization of the skeletal muscle pathology will be carried out in our newly generated R155C VCP/p97 knock-in mouse model.

人类 VCP/p97 基因突变会导致常染色体显性“伴有早发性佩吉特骨病和额颞叶痴呆的包涵体肌病”(IBMPFD) 和“肌萎缩侧索硬化症”(ALS) 变异。在第一个资助期间，我们生成并表征了一系列 VCP/p97 突变盘基网柄菌菌株，表征了 VCP/p97 单倍体不足的小鼠模型，并鉴定和表征了新型且与疾病相关的 VCP/p97 结合伴侣。在第二个资助期拟议的工作计划中，我们将扩展对VCP/p97的研究，特别强调IBMPFD的分子基础，采用广泛的实验程序，从生化和分子生物学实验、使用哺乳动物和盘基网柄菌细胞的细胞生物学测定到小鼠模型。我们将进一步鉴定新型 VCP/p97 结合伴侣，探索 VCP/p97 蛋白复合物内的分子相互作用，并分析自噬成分的表达变化。我们将阐明盘基网柄菌菌株中 R155C 突变体 VCP/p97 对蛋白酶体活性、自噬流和蛋白质聚集体组成的功能影响。相应的实验以及骨骼肌病理学的详细表征将在我们新生成的 R155C VCP/p97 敲入小鼠模型中进行。

项目成果

Proteasomal activity in skeletal muscle: a matter of assay design, muscle type, and age.

• DOI: 10.1016/j.ab.2009.12.026
• 发表时间: 2010-04
• 期刊: Analytical biochemistry
• 影响因子: 2.9
• 作者: K. Strucksberg;Karthikeyan Tangavelou;R. Schröder;C. Clemen

Mutant p97 exhibits species-specific changes of its ATPase activity and compromises the UBXD9-mediated monomerisation of p97 hexamers.

突变体 p97 表现出其 ATP 酶活性的物种特异性变化，并损害 UBXD9 介导的 p97 六聚体单体化

• DOI: 10.1016/j.ejcb.2016.03.004
• 发表时间: 2016
• 期刊: European journal of cell biology
• 影响因子: 6.6
• 作者: Rijal R;Arhzaouy K;Strucksberg K-H;Cross M;Hofmann A;Schröder R;Clemen CS;Eichinger L
• 通讯作者: Eichinger L

Genetic analysis of VCP and WASH complex genes in a German cohort of sporadic ALS-FTD patients

• DOI: 10.1016/j.neurobiolaging.2017.04.023
• 发表时间: 2017-08-01
• 期刊: NEUROBIOLOGY OF AGING
• 影响因子: 4.2
• 作者: Tuerk，Matthias;Schroeder，Rolf;Clemen，Christoph S.
• 通讯作者: Clemen，Christoph S.