Valosin-containing protein (VCP) is an AAA (ATPase associated with diverse cellular activities) ATPase that has been reported to participate in a wide variety of biological events. Studies of familial inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) have linked this disease to VCP mutations. However, the underlying molecular mechanism remains unclear. To address this question, we established a Drosophila IBMPFD model by tissue-specific expression of TER94 (Drosophila VCP homolog) mutants that correspond to VCP disease alleles. We provided evidence showing that IBMPFD-causing mutants are dominant-active alleles and may cause an imbalance of cellular ATP, which in turn perturb ATP-dependent processes within cells and progressively lead to the degeneration of tissues that demand higher energy expenditure.

​

While studying IBMPFD pathogenesis, we found that VCP/TER94 may have a potential role in maintaining the post-mitotic nuclear structure. The nucleus is the dedicated organelle in the eukaryotic cell where the genetic enigmas are stored and exploited for essentially every aspect of cellular activity. In most of the differentiated cells, the size and shape of their nuclei are remained in a quite stable status, whereas misshapen nuclei can be found in many aging-related diseases and cancerous tissues. We hope that this study could provide us an insight into the mechanism of VCP/TER94-mediated nuclear structure control and its relationship with carcinogenesis and normal aging process.