Identification of novel and disease related VCP binding partners and characterization of the skeletal muscle and cardiac pathology in a R155C-VCP knock-in mouse: a key to the understanding of human protein aggregate myopathies and cardiomyopathies

染色体9p13-p12上人类Valosin Holding Protein(VCP)基因的突变导致常染色体显性遗传性IBMPFD、伴随Paget病的包涵体肌病(IBM)和额颞痴呆(FD)或IBMPFD。除了首次描述了一种新型的VCP相关的额颞部痴呆，我们最近还首次报道了一种新型的VCP相关的心肌病。我们证明了IBMPFD横纹肌病理的形态特征是VCP和泛素阳性的细胞质和核蛋白聚集体。目前关于VCP相关IBMPFD的确证数据表明，该疾病的分子发病机制与泛素蛋白酶体蛋白降解系统的损伤有关。我们目前项目的主要目标是鉴定新的和疾病相关的VCP结合伙伴，并表征R155C-VCP敲入小鼠的骨骼肌和心脏病理。我们的项目致力于为IBMPFD和相关形式的蛋白质聚集性肌病和心肌病导致蛋白质聚集异常和进行性肌肉损伤的复杂分子机制提供新的见解。

Mutations of the human valosin containing protein (VCP) gene on chromosom 9p13-p12 cause autosomal dominant IBMPFD, inclusion body myopathy (IBM) associated with Paget disease of the bone (P) and frontotemporal dementia (FD) or IBMPFD. Beyond the first description of a novel type of VCP-related frontotemporal dementia, we recently provided the first report on a novel form of VCP-related cardiomyopathy. We demonstrated that the IBMPFD striated muscle pathology is morphologically characterized by VCP- and ubiquitin-positive cytoplasmic and nuclear protein aggregates. The corroborative data on VCP-related IBMPFD currently indicates that the molecular pathogenesis of the disorder is related to an impairment of the ubiquitin proteasome protein degradation system. The major goals of our current project are the identification of novel and disease related VCP binding partners and the characterization of the skeletal muscle and cardiac pathology in a R155C-VCP knock-in mouse. Our project strives to provide new insights in the complex molecular mechanisms leading to abnormal protein aggregation and progressive muscle damage in IBMPFD and related forms of protein aggregate myopathies and cardiomyopathies.