ID: ci011
Priority: P1
Status: in_progress
Valosin-Containing Protein (VCP), also known as p97 or CDC48 in yeast, is a highly conserved AAA+ ATPase essential for numerous cellular processes including protein degradation, endoplasmic reticulum-associated degradation (ERAD), autophagy, DNA repair, and membrane fusion[1]. VCP plays critical roles in maintaining cellular proteostasis, and mutations in the VCP gene are causally linked to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), inclusion body myopathy with early-onset Paget disease of bone (IBMPFD), and Parkinson's disease[2].
The VCP gene (also known as CDC48, TERATPASE) is located on chromosome 9p13.3 in humans and encodes a protein of 806 amino acids with a molecular weight of approximately 97 kDa[3]. The gene contains 17 exons spanning approximately 32 kb of genomic DNA.
VCP exhibits a characteristic AAA+ ATPase domain structure:
The protein forms a homohexameric complex, with each subunit containing an N-terminal domain and two ATPase domains (D1 and D2) arranged in a double-ring structure[4].
VCP/p97 is central to the ubiquitin-proteasome system (UPS):
VCP is essential for autophagic degradation:
VCP mutations are among the most common genetic causes of ALS[5]:
VCP is a major genetic cause of FTD[6]:
VCP dysfunction contributes to Parkinson's disease pathogenesis[7]:
| Strategy | Approach | Status |
|---|---|---|
| VCP inhibitors | Small molecules targeting ATPase activity | Preclinical |
| Autophagy enhancers | Promote clearance of protein aggregates | Clinical trials |
| Cofactor modulators | Npl4-UFD1 interaction blockers | Discovery |
| Gene therapy | AAV-mediated VCP modulation | Preclinical |
VCP is ubiquitously expressed with high levels in:
Meyer, H., Bug, M., & Bremer, S. (2012). Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system. Nature Cell Biology. 2012. ↩︎
Watts, G. D., et al. (2004). Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein. Nature Genetics. 2004. ↩︎
DeLaBarre, B., & Brunger, A. T. (2005). Nucleotide dependent motion and mechanism of action of p97/VCP. Journal of Molecular Biology. 2005. ↩︎
Johnson, J. O., et al. (2010). Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron. 2010. ↩︎
Forman, M. S., et al. (2006). Novel VCP mutations in Japanese patients with inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia. Journal of Neurology, Neurosurgery & Psychiatry. 2006. ↩︎
McGough, I. J., et al. (2017). Parkinson disease-associated mutations in VCP impair autophagic flux. Journal of Cell Biology. 2017. ↩︎