IBMPFD Mutations Impair Protein Degradation

描述(由申请人提供)：一种年龄相关性肌肉疾病是由于含有Valosin的蛋白(VCP)突变引起的IBMPFD/ALS或包涵体肌病(IBM)，与Paget‘s病(PDB)、额颞痴呆(FTD)和肌萎缩侧索硬化症(ALS)相关。肌肉无力是最常见的表型特征。虽然IBMPFD本身是罕见的，但每一个组成部分(IBM、PDB、FTD和ALS)的顶峰使其在普通人群中更常见。VCP突变破坏了自噬小体的成熟，导致自噬功能障碍和肌肉无力。此外，它们还会干扰mTORC1信号。我们建议1)鉴定VCP介导自噬所必需的分子复合体；2)了解VCP在氨基酸刺激mTORC1活性中的作用。3)调节mTORC1活性作为IBMPFD/ALS的治疗干预。这项提案将延续申请人过去5年的观察结果和发表的结果。

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.