VCP — Valosin-Containing Protein
VCP — Valosin-Containing Protein
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">VCP — Valosin-Containing Protein</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">VCP inhibitors</td>
<td>Small molecules targeting ATPase activity</td>
</tr>
<tr>
<td class="label">Autophagy enhancers</td>
<td>Promote clearance of protein aggregates</td>
</tr>
<tr>
<td class="label">Cofactor modulators</td>
<td>Npl4-UFD1 interaction blockers</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-mediated VCP modulation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/dementia" style="color:#ef9a9a">Dementia</a>, <a href="/wiki/frontotemporal-dementia" style="color:#ef9a9a">Frontotemporal Dementia</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">153 edges</a></td>
</tr>
</table>
ID: ci011
Priority: P1
Status: in_progress
Work Log
2026-03-14 06:05 PT — Slot 1
- Completed: Identified VCP (Valosin-Containing Protein) gene page as a short page (117 words) requiring expansion
- Status: in_progress
VCP — Valosin-Containing Protein
Overview
...VCP — Valosin-Containing Protein
VCP — Valosin-Containing Protein
<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">VCP — Valosin-Containing Protein</th>
</tr>
<tr>
<td class="label">Strategy</td>
<td>Approach</td>
</tr>
<tr>
<td class="label">VCP inhibitors</td>
<td>Small molecules targeting ATPase activity</td>
</tr>
<tr>
<td class="label">Autophagy enhancers</td>
<td>Promote clearance of protein aggregates</td>
</tr>
<tr>
<td class="label">Cofactor modulators</td>
<td>Npl4-UFD1 interaction blockers</td>
</tr>
<tr>
<td class="label">Gene therapy</td>
<td>AAV-mediated VCP modulation</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">Als</a>, <a href="/wiki/alzheimer" style="color:#ef9a9a">Alzheimer</a>, <a href="/wiki/amyotrophic-lateral-sclerosis" style="color:#ef9a9a">Amyotrophic Lateral Sclerosis</a>, <a href="/wiki/dementia" style="color:#ef9a9a">Dementia</a>, <a href="/wiki/frontotemporal-dementia" style="color:#ef9a9a">Frontotemporal Dementia</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">153 edges</a></td>
</tr>
</table>
ID: ci011
Priority: P1
Status: in_progress
Work Log
2026-03-14 06:05 PT — Slot 1
- Completed: Identified VCP (Valosin-Containing Protein) gene page as a short page (117 words) requiring expansion
- Status: in_progress
VCP — Valosin-Containing Protein
Overview
Mermaid diagram (expand to render)
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](/entities/autophagy), DNA repair, and membrane fusion["@meyer2012"]. 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["@watts2004"].
Gene and Protein Structure
Gene Organization
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[@kobayashi2000]. The gene contains 17 exons spanning approximately 32 kb of genomic DNA.
Protein Domain Architecture
VCP exhibits a characteristic AAA+ ATPase domain structure:
N-terminal Domain (1-200 aa): Contains the Npl4-UFD1 cofactor binding site and regulatory interfaces
D1 ATPase Domain (200-460 aa): First ATPase domain with Walker A (P-loop) and Walker B motifs
D2 ATPase Domain (460-760 aa): Second ATPase domain: responsible for the primary hexameric ring's ATPase activity
C-terminal Domain (760-806 aa): Contains the final α-helical region and serves as a binding platform for various cofactorsThe 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[@delabarre2005].
Biological Functions
Protein Degradation
VCP/p97 is central to the [ubiquitin-proteasome system](/cell-types/ubiquitin-proteasome-system) (UPS):
- ERAD: VCP extracts misfolded proteins from the endoplasmic reticulum for proteasomal degradation
- Ubiquitin Chain Processing: VCP recognizes and processes K48-linked polyubiquitin chains for substrate delivery
- Proteasome Recruitment: Facilitates substrate loading onto the 19S regulatory particle
Autophagy
VCP is essential for autophagic degradation:
- Autophagosome-lysosome fusion: Mediates membrane trafficking events required for autophagosome maturation
- Selective autophagy: VCP recruits autophagy receptors and facilitates cargo recognition
- Aggresome clearance: VCP dysfunction leads to accumulation of aggresomes and protein aggregates
Membrane Dynamics
- Nuclear envelope reconstruction: Required for post-mitotic nuclear envelope reassembly
- ER network maintenance: Regulates ER morphology and contact sites
- Golgi re-assembly: Facilitates Golgi stack reformation after mitosis
DNA Repair
- Double-strand break repair: VCP participates in ubiquitin-dependent DNA damage response
- Replication fork restart: Facilitates repair of stalled replication forks
Role in Neurodegenerative Diseases
Amyotrophic Lateral Sclerosis (ALS)
VCP mutations are among the most common genetic causes of ALS[@johnson2010]:
- Prevalence: VCP mutations account for 1-2% of familial ALS cases and rare sporadic cases
- Pathogenic mutations: Over 50 pathogenic mutations identified (e.g., R155H, R191Q, A232E, R155P)
- Mechanisms:
- Impaired autophagy leading to protein aggregate accumulation
- Disrupted RNA metabolism
- Mitochondrial dysfunction
- Dysregulated stress granule dynamics
- Phenotype: Typical ALS presentation with combined upper/lower motor neuron involvement; some patients develop FTD
Frontotemporal Dementia (FTD)
VCP is a major genetic cause of FTD[@forman2006]:
- VCP-Associated FTD: Characterized by behavioral variant FTD with prominent personality changes
- Neuropathology: [TDP-43](/mechanisms/tdp-43-proteinopathy) positive inclusions in [neurons](/entities/neurons) and glia
- Overlap with ALS: Up to 15% of VCP mutation carriers develop both ALS and FTD
Inclusion Body Myopathy with Paget Disease of Bone (IBMPFD)
- Triad: VCP mutations cause a combination of myopathy, bone disease (Paget), and dementia
- Myopathy: Progressive proximal muscle weakness beginning in the fourth to sixth decade
- Bone: Osteitis deformans affecting pelvis, spine, and long bones
Parkinson's Disease
VCP dysfunction contributes to Parkinson's disease pathogenesis[@mcgough2017]:
- [α-Synuclein](/proteins/alpha-synuclein) metabolism: VCP regulates autophagic degradation of α-synuclein
- Mitochondrial quality control: VCP-mediated mitophagy is impaired in PD models
- LRRK2 interaction: VCP interacts with G2019S LRRK2 mutants
Other Neurodegenerative Diseases
- Alzheimer's Disease: VCP activity modulates [APP](/entities/app-protein) processing and [Aβ](/proteins/amyloid-beta) clearance
- Huntington's Disease: VCP regulates mutant [huntingtin](/proteins/huntingtin) clearance
- Charcot-Marie-Tooth Disease: VCP mutations cause peripheral neuropathy
Therapeutic Implications
Pharmacological Targets
Biomarker Potential
- VCP activity: Peripheral blood mononuclear cell VCP ATPase activity as a disease biomarker
- CSF biomarkers: VCP levels in cerebrospinal fluid correlate with disease progression
Expression Pattern
Brain Regional Distribution
VCP is ubiquitously expressed with high levels in:
- Motor [cortex](/brain-regions/cortex) and spinal cord motor neurons
- Hippocampal CA1 pyramidal neurons
- Substantia nigra dopaminergic neurons
- Cerebellar Purkinje cells
Cellular Expression
- Neurons: High expression in somas and axons
- Glia: Moderate expression in [astrocytes](/entities/astrocytes) and [microglia](/cell-types/microglia-neuroinflammation)
- Synaptic terminals: Enriched in presynaptic terminals
Cross-Linking
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
- [Parkinson's Disease](/diseases/parkinsons-disease)
- [Alzheimer's Disease](/diseases/alzheimers-disease)
- [Protein Degradation Pathways](/mechanisms/ubiquitin-proteasome-system)
- [Autophagy in Neurodegeneration](/mechanisms/autophagy-lysosomal-pathway)
- [ER Stress and UPR](/mechanisms/er-stress-unfolded-protein-response)
- [TDP-43 Proteinopathy](/mechanisms/tdp-43-proteinopathy)
See Also
- [Inclusion Body Myopathy with Paget Disease of Bone and Frontotemporal Dementia (IBMPFD)](/diseases/frontotemporal-disease)
- [Frontotemporal Dementia](/diseases/frontotemporal-dementia)
- [Amyotrophic Lateral Sclerosis](/diseases/amyotrophic-lateral-sclerosis)
- [VCP ATPase](/genes/cp)
- [Protein Aggregation in Neurodegeneration](/diseases/neurodegeneration)
External Links
- [PubMed - VCP Neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/?term=VCP+neurodegeneration)
- [OMIM - VCP](https://www.omim.org/entry/601023)
References
[Unknown, Meyer, H., Bug, M., & Bremer, S. (2012). Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system (2012)](https://pubmed.ncbi.nlm.nih.gov/22298039/)
[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 (2004)](https://pubmed.ncbi.nlm.nih.gov/15034582/)
[Kobayashi, T., et al, (2000) (2000)](https://pubmed.ncbi.nlm.nih.gov/10831902/)
[Unknown, DeLaBarre, B., & Brunger, A. T. (2005). Nucleotide dependent motion and mechanism of action of p97/VCP (2005)](https://pubmed.ncbi.nlm.nih.gov/15740739/)
[Johnson, J. O., et al., (2010). Exome sequencing reveals VCP mutations as a cause of familial ALS (2010)](https://pubmed.ncbi.nlm.nih.gov/21145000/)
[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 (2006)](https://pubmed.ncbi.nlm.nih.gov/16735456/)
[McGough, I. J., et al., (2017). Parkinson disease-associated mutations in VCP impair autophagic flux (2017)](https://pubmed.ncbi.nlm.nih.gov/29021225/)Pathway Diagram
The following diagram shows the key molecular relationships involving VCP — Valosin-Containing Protein discovered through SciDEX knowledge graph analysis:
Mermaid diagram (expand to render)