IBMPFD Mutations Impair Protein Degradation

描述（由申请人提供）：一种年龄相关的肌肉疾病是由于含缬沙宁蛋白（VCP）的突变引起的，该突变导致IBMPFD/ALS或与骨佩吉特病（PDB）、额颞叶痴呆（FTD）和肌萎缩侧索硬化（ALS）相关的包涵体肌病（IBM）。肌无力是最普遍的表型特征。虽然IBMPFD本身是罕见的，但每个组成部分（IBM，PDB，FTD和ALS）的高潮使其在一般人群中的发病率更常见。VCP突变破坏自噬体成熟，导致功能失调的自噬和肌肉无力。此外，它们破坏mTORC 1信号传导。我们建议1）确定VCP介导自噬所必需的分子复合物; 2）了解VCP在氨基酸刺激mTORC 1活性中的作用。3)调节mTORC 1活性作为IBMPFD/ALS的治疗干预。该提案将扩展申请人在过去5年中的观察和公布结果。

DESCRIPTION (provided by applicant): One age associated muscle disorder is due to mutations in valosin containing protein (VCP) which causes IBMPFD/ALS or inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB), fronto-temporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Muscle weakness is the most prevalent phenotypic feature. Although IBMPFD itself is rare, the culmination of each component (IBM, PDB, FTD and ALS) makes its incidence more common in the general population. VCP mutations disrupt autophagosome maturation resulting in dysfunctional autophagy and muscle weakness. In addition, they disrupt mTORC1 signaling. We propose to 1) identify the molecular complex essential for VCP mediation autophagy; 2) understand the role for VCP in amino acid stimulated mTORC1 activity. 3) Modulate mTORC1 activity as a therapeutic intervention in IBMPFD/ALS. This proposal will extend the observations and published results from the applicant over the past 5 years.