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

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 从而促进细胞凋亡。 p97 AAA ATPase（也称为 VCP、CDC48、TER ATPase）在 多种生物过程，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 p97 失调在蛋白质错误折叠、聚集和加工中的重要性并支持其参与 错误，最终导致细胞死亡。 p97/VCP 中的单个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 (FTD) 和一种称为遗传性额颞叶痴呆的特殊病症 包涵体肌病伴佩吉特骨病加 ALS（一种运动神经元疾病，也称为 Lou） 伽雷克氏病。突变源可能是遗传的、环境的、自发的或与年龄相关的。目标是 该项目旨在确定关键的致病机制，用于开发精准疗法以纠正 由于 p97 疾病突变导致的缺陷，但不损害正常的 p97 功能。我们的中心假设：p97 疾病突变体具有异常构象，这反过来又导致蛋白质相互作用组的改变，在特定情况下 包括神经元细胞在内的细胞引起致病作用 检验这一假设并确定关键致病因素 可以作为治疗干预目标的机制，我们建议比较 WT 的相互作用组 和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 和生化方法来确定改变的相互作用因子在调节 p97 ATP 酶活性中的作用 以及调节疾病表型。总体而言，如何开发突变靶向的新范例 神经退行性疾病的治疗方法——尤其是 ATP 酶蛋白家族的致病突变体—— 将成立。

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.