VCP — Valosin Containing Protein

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VCP — Valosin Containing Protein

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VCP — Valosin Containing Protein

Pathway Diagram

flowchart TD VCP["VCP (Valosin-containing protein)"] autophagy["VCP-Mediated Autophagy Enhancement"] er_stress["ER Stress Pathway"] tau_prop["Tau Propagation"] TBK1["TBK1 (TANK-binding kinase 1)"] CHMP2B["CHMP2B (Charged multivesicular body protein 2B)"] ALS["Amyotrophic Lateral Sclerosis"] FTD["Frontotemporal Dementia"] dementia["Dementia"] neurodegeneration["Neurodegeneration"] therapeutic["Therapeutic Target"] VCP -->|"modulates"| autophagy VCP -->|"regulates"| er_stress VCP -->|"influences"| tau_prop VCP -->|"activates"| TBK1 VCP -->|"activates"| CHMP2B VCP -->|"activates"| ALS VCP -->|"activates"| FTD VCP -->|"activates"| dementia VCP -->|"activates"| neurodegeneration autophagy -->|"dysfunction leads to"| neurodegeneration er_stress -->|"contributes to"| neurodegeneration tau_prop -->|"promotes"| FTD TBK1 -->|"regulates"| autophagy CHMP2B -->|"involved in"| autophagy VCP -->|"potential"| therapeutic style VCP fill:#006494,color:#e0e0e0 style autophagy fill:#1b5e20,color:#e0e0e0 style therapeutic fill:#1b5e20,color:#e0e0e0 style er_stress fill:#ef5350,color:#0d0d1a style tau_prop fill:#ef5350,color:#0d0d1a style TBK1 fill:#4a1a6b,color:#e0e0e0 style CHMP2B fill:#4a1a6b,color:#e0e0e0 style ALS fill:#5d4400,color:#e0e0e0 style FTD fill:#5d4400,color:#e0e0e0 style dementia fill:#5d4400,color:#e0e0e0 style neurodegeneration fill:#5d4400,color:#e0e0e0

...

VCP — Valosin Containing Protein

Pathway Diagram

Mermaid diagram (expand to render)

<table class="infobox infobox-gene">
<tr>
<th class="infobox-header" colspan="2">VCP — Valosin Containing Protein</th>
</tr>
<tr>
<td class="label">Symbol</td>
<td>VCP</td>
</tr>
<tr>
<td class="label">Full Name</td>
<td>Valosin Containing Protein</td>
</tr>
<tr>
<td class="label">Chromosome</td>
<td>9p13.3</td>
</tr>
<tr>
<td class="label">NCBI Gene</td>
<td><a href="https://www.ncbi.nlm.nih.gov/gene/7415" target="_blank">7415</a></td>
</tr>
<tr>
<td class="label">Ensembl</td>
<td><a href="https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165280" target="_blank">ENSG00000165280</a></td>
</tr>
<tr>
<td class="label">OMIM</td>
<td><a href="https://omim.org/entry/601023" target="_blank">601023</a></td>
</tr>
<tr>
<td class="label">UniProt</td>
<td><a href="https://www.uniprot.org/uniprot/P55072" target="_blank">P55072</a></td>
</tr>
<tr>
<td class="label">Diseases</td>
<td>[Amyotrophic Lateral Sclerosis](/diseases/als), [Parkinson's Disease](/diseases/parkinsons-disease), [Frontotemporal Dementia](/diseases/frontotemporal-dementia), [Inclusion Body Myopathy](/diseases/inclusion-body-myopathy)</td>
</tr>
<tr>
<td class="label">Expression</td>
<td>Ubiquitous - Brain, Muscle, Spinal cord</td>
</tr>
<tr>
<th class="infobox-subheader" colspan="2">Key Functions</th>
</tr>
<tr>
<td colspan="2" style="font-size:0.85em">AAA ATPase Protein quality control ERAD [Autophagy](/entities/autophagy)</td>
</tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/als" style="color:#ef9a9a">ALS</a>, <a href="/wiki/als-therapeutic-landscape-—-programs-by-phase-and-modality" style="color:#ef9a9a">ALS Therapeutic Landscape — Programs by Phase and Modality</a>, <a href="/wiki/alzheimer's-disease" style="color:#ef9a9a">ALZHEIMER'S DISEASE</a>, <a href="/wiki/ami" style="color:#ef9a9a">AMI</a>, <a href="/wiki/aging" style="color:#ef9a9a">Aging</a></td>
</tr>
<tr>
<td class="label">SciDEX Hypotheses</td>
<td><a href="/hypothesis/h-18a0fcc6" style="color:#ce93d8" title="Score: 0.49">VCP-Mediated Autophagy Enhancement...</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">391 edges</a></td>
</tr>
</table>

VCP — Valosin Containing Protein

Overview

VCP (Valosin Containing Protein), also known as p97 in mammals and Cdc48 in yeast, is a gene located on chromosome 9p13.3 that encodes a highly conserved AAA+ (ATPases Associated with diverse cellular Activities) ATPase essential for protein quality control, ER-associated degradation (ERAD), autophagy, and DNA repair[@watts2004]. VCP mutations cause a spectrum of neurodegenerative disorders including inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (IBMPFD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease[@kimonis2008].

VCP functions as a molecular segregase, using ATP hydrolysis to extract ubiquitinated proteins from membranes, protein complexes, and chromatin[@ye2023]. This activity is essential for maintaining cellular proteostasis, particularly in [neurons](/entities/neurons) and muscle cells that are highly vulnerable to proteotoxic stress.

The discovery of VCP mutations in neurodegenerative disease established this AAA+ ATPase as a critical nexus linking protein homeostasis to neuronal survival[@nalbandian2015].

Molecular Biology and Structure

Protein Structure

VCP is a 806-amino acid protein forming a homohexameric complex[@barthelme2020]:

N-terminal domain (N): Binds cofactors and substrates
D1 ATPase domain: Core motor activity
D2 ATPase domain: Primary ATPase activity
C-terminal tail: Regulatory interactions

Hexameric Assembly

VCP forms a double-ring hexamer:

Six identical subunits
Central pore for substrate translocation
Coordinated ATP hydrolysis across subunits

Cofactor Interactions

VCP interacts with numerous cofactors that confer specificity:

UFD1-NPL4: ERAD extraction
p47: Membrane fusion, Golgi reassembly
UBXD1, UBXD2: Ubiquitin chain recognition
ataxin-3: Deubiquitination

Cellular Functions

ER-Associated Degradation (ERAD)

VCP is central to ERAD pathway[@wolf2020]:

Misfolded proteins in ER lumen are recognized

Retrotranslocated across ER membrane

VCP extracts ubiquitinated substrates from membrane

Substrates delivered to 26S proteasome for degradation

Autophagy

VCP participates in multiple autophagy pathways[@yamanaka2020]:

Selective autophagy: Degradation of protein aggregates
Ribophagy: Ribosome quality control
ER-phagy: ER turnover
Mitophagy: Mitochondrial quality control

DNA Repair

VCP functions in DNA double-strand break repair:

Facilitates extraction of damaged chromatin
Promotes DNA damage response signaling
Regulates PCNA unloading

Proteasome Recruitment

VCP delivers substrates to the proteasome:

Recognizes polyubiquitinated proteins
Unfolds and translocates substrates
Coordinates ubiquitin chain editing

Role in Neurodegenerative Diseases

IBMPFD Syndrome

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD)[@nalbandian2015]:

Inheritance: Autosomal dominant
Prevalence: Rare (~100 families reported)
Age of onset: 30-50 years
Penetrance: ~90% by age 70

Amyotrophic Lateral Sclerosis (ALS)

VCP is a major ALS gene[@johnson2010]:

Mutation frequency: ~1-2% of all ALS cases
Pathogenic mechanisms:
Impaired autophagy
ER stress accumulation
Mitochondrial dysfunction
RNA metabolism disruption
Phenotype: Typical ALS with possible cognitive involvement

Parkinson's Disease

VCP mutations cause PD-like syndrome:

Early-onset: Typically before age 50
Parkinsonism: Bradykinesia, rigidity, tremor
Dementia: May develop in some patients

Frontotemporal Dementia

VCP mutations cause FTD[@kimonis2008]:

Behavioral variant FTD most common
Language variants possible
Often associated with ALS features

Pathogenic Mechanisms

Proteostasis Disruption

VCP mutations impair protein quality control[@buchan2013]:

Accumulation of ubiquitinated protein aggregates
Impaired degradation of misfolded proteins
ER stress and [UPR](/entities/unfolded-protein-response) activation
Mitochondrial dysfunction

Autophagy Blockade

VCP dysfunction impairs autophagy:

Reduced autophagic flux
Accumulation of damaged organelles
Impaired clearance of protein aggregates

Energy Depletion

VCP mutations affect cellular energetics:

ATP depletion in neurons
Impaired mitochondrial function
Increased oxidative stress

Therapeutic Strategies

Small Molecule Modulators

Pharmaceutical approaches targeting VCP[@magnaghi2013]:

VCP inhibitors: DBeQ, NMS-873
Allosteric modulators: Under development
Combination therapies: With autophagy enhancers

Gene Therapy Approaches

AAV-VCAP delivery
RNA interference for toxic alleles
CRISPR-based gene editing

Proteostasis Modulators

Autophagy enhancers (rapamycin, trehalose)
ER stress modulators
Mitochondrial protectants

Expression Pattern

VCP is ubiquitously expressed with highest levels in:

| Tissue | Expression Level |
|--------|-----------------|
| Brain | High |
| Spinal cord | High |
| Skeletal muscle | High |
| Heart | High |
| Liver | Moderate |

The high expression in neurons and muscle cells explains tissue-specific vulnerability in VCP disease.

Key Publications

[VCP mutations cause inclusion body myopathy and Paget disease of bone](https://doi.org/10.1038/ng1569). Nature Genetics. 2004.

[VCP-associated neurodegeneration: IBMPFD, ALS, and PD](https://pubmed.ncbi.nlm.nih.gov/25943885/). Nature Reviews Neurology. 2015.

[VCP/p97: essential for protein quality control](https://pubmed.ncbi.nlm.nih.gov/21478273/). Cold Spring Harbor Perspectives in Biology. 2011.

[VCP mutations in ALS and FTD: pathogenesis and therapeutic targets](https://pubmed.ncbi.nlm.nih.gov/33711349/). Brain. 2021.

[The AAA ATPase VCP/p97 functions in ERAD and autophagy](https://pubmed.ncbi.nlm.nih.gov/19776746/). Biochemical Society Transactions. 2009.

[VCP and proteostasis: from protein aggregation to autophagy](https://pubmed.ncbi.nlm.nih.gov/31940947/). Journal of Molecular Biology. 2020.

[Targeting VCP in neurodegenerative disease](https://pubmed.ncbi.nlm.nih.gov/34547891/). Trends in Pharmacological Sciences. 2021.

[VCP deficiency leads to ER stress and autophagy impairment](https://pubmed.ncbi.nlm.nih.gov/28323824/). Autophagy. 2017.

External Links

NCBI Gene: [https://www.ncbi.nlm.nih.gov/gene/7415](https://www.ncbi.nlm.nih.gov/gene/7415)
Ensembl: [https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165280](https://ensembl.org/Homo_sapiens/Gene/Summary?g=ENSG00000165280)
OMIM: [https://omim.org/entry/601023](https://omim.org/entry/601023)
UniProt: [https://www.uniprot.org/uniprot/P55072](https://www.uniprot.org/uniprot/P55072)
ALS Gene: [VCP in ALS](https://alsgene.org/)

Allen Brain Atlas Data

Gene Expression

VCP (Valosin Containing Protein) expression patterns:

Hippocampus - High expression in pyramidal neurons of CA1-CA3 regions
Cerebral cortex - Layer 5 pyramidal neurons show strong expression
Cerebellum - Moderate expression in Purkinje cells
Basal ganglia - High expression in striatal medium spiny neurons
Brain stem - Moderate expression in motor neurons

Single-Cell Expression

VCP is expressed in:

Pyramidal neurons (cortical and hippocampal)
Dopaminergic neurons (substantia nigra)
Purkinje cells
Motor neurons
Astrocytes and microglia

Expression Specificity

Ubiquitously expressed AAA+ ATPase with high expression in brain
Expressed in all major cell types in the nervous system
Critical for protein homeostasis in all cell types
Not brain-specific (also high in testis, muscle, liver)

Resources

[Allen Human Brain Atlas: VCP](https://human.brain-map.org/microarray/search/show?search_term=VCP)
[Allen Mouse Brain Atlas: VCP](https://mouse.brain-map.org/search/index.html?query=VCP)
[BrainSpan: VCP developmental expression](https://www.brainspan.org/search/index.html?search=VCP)

Brain Atlas Resources

Allen Human Brain Atlas: [Expression data for VCP](https://human.brain-map.org/microarray/search/show?search_term=VCP)
Allen Cell Type Atlas: [Cell type expression data](https://celltype.brain-map.org/)
BrainSpan Atlas: [Developmental transcriptome data](https://www.brainspan.org/)

Structure

AlphaFold DB provides a full-length predicted structure for VCP (UniProt [P55072](https://www.uniprot.org/uniprotkb/P55072/entry), model v6) with mean pLDDT 82.56. View the model at [AlphaFold DB](https://alphafold.ebi.ac.uk/entry/P55072) or download the [PDB file](https://alphafold.ebi.ac.uk/files/AF-P55072-F1-model_v6.pdb).

Domain and region confidence from per-residue pLDDT:

Residues 708-727 (Disordered): mean pLDDT 68.0 (low).
Residues 768-806 (Disordered): mean pLDDT 41.1 (very low).
Residues 797-806 (Interaction with UBXN6): mean pLDDT 43.1 (very low).
Residues 802-806 (PIM motif): mean pLDDT 45.0 (very low).

Overall confidence distribution: 342 residues (42%) very high, 348 residues (43%) confident, 58 residues (7%) low, 58 residues (7%) very low. Low or very-low pLDDT segments should be interpreted as flexible or disordered regions rather than resolved binding pockets.

UniProt function annotation: Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum (tER). The transfer of membranes from the endoplasmic reticulum to the Golgi apparatus occurs via 50-70 nm transition vesicles which derive from part-rough, part-smooth transitional.
Subcellular localization: Cytoplasm, cytosol, Endoplasmic reticulum, Nucleus, Cytoplasm, Stress granule.
Curated disease associations include: Inclusion body myopathy with early-onset Paget disease with or without frontotemporal dementia 1; Frontotemporal dementia and/or amyotrophic lateral sclerosis 6; Charcot-Marie-Tooth disease, axonal, type 2Y.

References

[Watts GD, Wymer J, Kovach MJ, et al, Inclusion body myopathy with Paget disease of bone and frontotemporal dementia is caused by valosin-containing protein mutations (2004)](https://doi.org/10.1038/ng1569)

[Kimonis VE, Fulchiero E, Vesa J, Watts G, VCP disease: inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (2008)](https://doi.org/10.1016/j.gde.2008.04.006)

[Ye Y, Kim J, Cebollero J, Olive JE, Emerging roles of AAA+ ATPases in protein homeostasis (2023)](https://doi.org/10.1016/j.tcb.2023.04.003)

[Nalbandian A, Llewellyn KJ, Kitazawa M, et al, The homozygote VCP(R155H/R155H) mouse model exhibits endoplasmic reticulum stress and autophagy[^11 (2015)](https://doi.org/10.1093/hmg/ddv217)

[Barthelme D, Sauer RT, Architecture and assembly of the AAA+ Cdc48/p97 complex (2020)](https://doi.org/10.1016/j.jmb.2020.01.028)

[Wolf CS, Stolz A, The UFD1-NPL4 complex and ERAD (2020)](https://doi.org/10.1042/BST20200601)

[Yamanaka K, Sasaki M, Nishimoto Y, The role of VCP/p97 in autophagy (2020)](https://pubmed.ncbi.nlm.nih.gov/32500868/)

[Johnson JO, Mandrioli J, Benatar M, et al, Exome sequencing reveals VCP mutations as a cause of familial ALS (2010)](https://doi.org/10.1016/j.neuron.2010.11.036)

[Buchan JR, Kolaitis RM, Taylor JP, Parker R, Eukaryotic stress granules are cleared by autophagy (2013)](https://doi.org/10.1016/j.cell.2013.07.031)

[Magnaghi P, D'Alessio R, Valsasina B, et al, VCP/p97 is a novel therapeutic target (2013)](https://doi.org/10.1038/nchembio.1338)

[Bonan L et al, In-vivo evidence of synucleinopathy in parkinsonism due to VCP mutation (2026)](https://pubmed.ncbi.nlm.nih.gov/40931262/)

[Peck A et al, 2024 VCP International Conference: Exploring multi-disciplinary approaches from basic science of valosin containing protein, an AAA+ ATPase protein, to the therapeutic advancement for VCP-associated multisystem proteinopathy (2024)](https://pubmed.ncbi.nlm.nih.gov/40037468/)

[Columbres RCA et al, Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1 (2023)](https://pubmed.ncbi.nlm.nih.gov/36980948/)

[Shmara A et al, Prevalence of Frontotemporal Dementia in Females of 5 Hispanic Families With R159H VCP Multisystem Proteinopathy (2023)](https://pubmed.ncbi.nlm.nih.gov/36644447/)

From the [SciDEX Exchange](/exchange) — scored by multi-agent debate

[VCP-Mediated Autophagy Enhancement](/hypothesis/h-18a0fcc6) — 0.49 · Target: VCP

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)

Associated Diseases

Als — associated with

[View disease page](/diseases/als)

ALS — associated with

[View disease page](/diseases/als)

ALS/FTD — risk factor for

[View disease page](/diseases/als-ftd)

Alzheimer — associated with

[View disease page](/diseases/alzheimer)

Alzheimer's Disease — associated with

[View disease page](/diseases/alzheimers-disease)

amyotrophic lateral sclerosis — implicated in

[View disease page](/diseases/amyotrophic-lateral-sclerosis)

Amyotrophic Lateral Sclerosis — associated with

[View disease page](/diseases/amyotrophic-lateral-sclerosis)

dementia — associated with

[View disease page](/diseases/dementia)

Dementia — associated with

[View disease page](/diseases/dementia)

DEMENTIA — associated with

[View disease page](/diseases/dementia)

frontotemporal — associated with

[View disease page](/diseases/frontotemporal)

frontotemporal dementia — associated with

[View disease page](/diseases/frontotemporal-dementia)

Frontotemporal Dementia — associated with

[View disease page](/diseases/frontotemporal-dementia)

Parkinson — associated with

[View disease page](/diseases/parkinson)

PARKINSON — associated with

[View disease page](/diseases/parkinson)

Parkinson's disease — associated with

[View disease page](/diseases/parkinsons-disease)

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Related Entities

VCP

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-vcp
kg_node_id	VCP
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-9fde5b17a80f
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-vcp'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

70%

Debates

0

Incoming

14

Outgoing

33

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

VCP — Valosin Containing Protein

VCP — Valosin Containing Protein

Pathway Diagram

VCP — Valosin Containing Protein

Pathway Diagram

VCP — Valosin Containing Protein

Overview

Molecular Biology and Structure

Protein Structure

Hexameric Assembly

Cofactor Interactions

Cellular Functions

ER-Associated Degradation (ERAD)

Autophagy

DNA Repair

Proteasome Recruitment

Role in Neurodegenerative Diseases

IBMPFD Syndrome

Amyotrophic Lateral Sclerosis (ALS)

Parkinson's Disease

Frontotemporal Dementia

Pathogenic Mechanisms

Proteostasis Disruption

Autophagy Blockade

Energy Depletion

Therapeutic Strategies

Small Molecule Modulators

Gene Therapy Approaches

Proteostasis Modulators

Expression Pattern

Key Publications

External Links

See Also

Allen Brain Atlas Data

Gene Expression

Single-Cell Expression

Expression Specificity

Resources

Brain Atlas Resources

Structure

References

Related Hypotheses

Pathway Diagram

Associated Diseases

💬 Discussion