| Symbol |
VCP |
| Full Name |
Valosin Containing Protein |
| Chromosome |
9p13.3 |
| NCBI Gene |
7415 |
| Ensembl |
ENSG00000165280 |
| OMIM |
601023 |
| UniProt |
P55072 |
| Diseases |
[Amyotrophic Lateral Sclerosis](/diseases/als), [Parkinson's Disease](/diseases/parkinsons-disease), [Frontotemporal Dementia](/diseases/frontotemporal-dementia), [Inclusion Body Myopathy](/diseases/inclusion-body-myopathy) |
| Expression |
Ubiquitous - Brain, Muscle, Spinal cord |
AAA ATPase
Protein quality control
ERAD
[Autophagy](/entities/autophagy) |
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 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
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
VCP forms a double-ring hexamer:
- Six identical subunits
- Central pore for substrate translocation
- Coordinated ATP hydrolysis across subunits
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
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
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
VCP functions in DNA double-strand break repair:
- Facilitates extraction of damaged chromatin
- Promotes DNA damage response signaling
- Regulates PCNA unloading
VCP delivers substrates to the proteasome:
- Recognizes polyubiquitinated proteins
- Unfolds and translocates substrates
- Coordinates ubiquitin chain editing
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
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
VCP mutations cause PD-like syndrome:
- Early-onset: Typically before age 50
- Parkinsonism: Bradykinesia, rigidity, tremor
- Dementia: May develop in some patients
VCP mutations cause FTD[@kimonis2008]:
- Behavioral variant FTD most common
- Language variants possible
- Often associated with ALS features
VCP mutations impair protein quality control[@buchan2013]:
- Accumulation of ubiquitinated protein aggregates
- Impaired degradation of misfolded proteins
- ER stress and UPR activation
- Mitochondrial dysfunction
VCP dysfunction impairs autophagy:
- Reduced autophagic flux
- Accumulation of damaged organelles
- Impaired clearance of protein aggregates
VCP mutations affect cellular energetics:
- ATP depletion in neurons
- Impaired mitochondrial function
- Increased oxidative stress
Pharmaceutical approaches targeting VCP[@magnaghi2013]:
- VCP inhibitors: DBeQ, NMS-873
- Allosteric modulators: Under development
- Combination therapies: With autophagy enhancers
- AAV-VCAP delivery
- RNA interference for toxic alleles
- CRISPR-based gene editing
- Autophagy enhancers (rapamycin, trehalose)
- ER stress modulators
- Mitochondrial protectants
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.
- VCP mutations cause inclusion body myopathy and Paget disease of bone. Nature Genetics. 2004.
- VCP-associated neurodegeneration: IBMPFD, ALS, and PD. Nature Reviews Neurology. 2015.
- VCP/p97: essential for protein quality control. Cold Spring Harbor Perspectives in Biology. 2011.
- VCP mutations in ALS and FTD: pathogenesis and therapeutic targets. Brain. 2021.
- The AAA ATPase VCP/p97 functions in ERAD and autophagy. Biochemical Society Transactions. 2009.
- VCP and proteostasis: from protein aggregation to autophagy. Journal of Molecular Biology. 2020.
- Targeting VCP in neurodegenerative disease. Trends in Pharmacological Sciences. 2021.
- VCP deficiency leads to ER stress and autophagy impairment. Autophagy. 2017.
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
VCP is expressed in:
- Pyramidal neurons (cortical and hippocampal)
- Dopaminergic neurons (substantia nigra)
- Purkinje cells
- Motor neurons
- Astrocytes and microglia
- 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)
- 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)
- Kimonis VE, Fulchiero E, Vesa J, Watts G, VCP disease: inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (2008)
- Ye Y, Kim J, Cebollero J, Olive JE, Emerging roles of AAA+ ATPases in protein homeostasis (2023)
- [Nalbandian A, Llewellyn KJ, Kitazawa M, et al, The homozygote VCP(R155H/R155H) mouse model exhibits endoplasmic reticulum stress and autophagy^11 (2015)
- Barthelme D, Sauer RT, Architecture and assembly of the AAA+ Cdc48/p97 complex (2020)
- Wolf CS, Stolz A, The UFD1-NPL4 complex and ERAD (2020)
- Yamanaka K, Sasaki M, Nishimoto Y, The role of VCP/p97 in autophagy (2020)
- Johnson JO, Mandrioli J, Benatar M, et al, Exome sequencing reveals VCP mutations as a cause of familial ALS (2010)
- Buchan JR, Kolaitis RM, Taylor JP, Parker R, Eukaryotic stress granules are cleared by autophagy (2013)
- Magnaghi P, D'Alessio R, Valsasina B, et al, VCP/p97 is a novel therapeutic target (2013)
- Bonan L et al, In-vivo evidence of synucleinopathy in parkinsonism due to VCP mutation (2026)
- 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)
- Columbres RCA et al, Novel Variants in the VCP Gene Causing Multisystem Proteinopathy 1 (2023)
- Shmara A et al, Prevalence of Frontotemporal Dementia in Females of 5 Hispanic Families With R159H VCP Multisystem Proteinopathy (2023)