Valosin-containing protein (VCP), also known as p97, is a highly conserved AAA+ ATPase that plays critical roles in protein homeostasis, autophagy, and cellular stress responses. VCP mutations cause VCP-associated multisystem proteinopathy (MSP), characterized by inclusion body myopathy, Paget disease of bone, and frontotemporal dementia (IBMPFD). Additionally, VCP dysfunction is strongly implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) pathogenesis. VCP-targeted therapy represents a promising therapeutic approach for these devastating neurodegenerative conditions. [@vcp2022]
Valosin-containing protein (VCP), also known as p97, is a highly conserved AAA+ ATPase that plays critical roles in protein homeostasis, autophagy, and cellular stress responses. VCP mutations cause VCP-associated multisystem proteinopathy (MSP), characterized by inclusion body myopathy, Paget disease of bone, and frontotemporal dementia (IBMPFD). Additionally, VCP dysfunction is strongly implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) pathogenesis. VCP-targeted therapy represents a promising therapeutic approach for these devastating neurodegenerative conditions. [@vcp2022]
Mechanism of Action
p97/VCP ATPase Inhibition
VCP/p97 is a hexameric AAA+ ATPase that unfolds and translocates polyubiquitinated substrates through its central channel. Inhibiting VCP ATPase activity disrupts multiple cellular processes that become dysregulated in disease: [@vcpp2021]
Proteasomal degradation: VCP extracts ubiquitinated proteins from the endoplasmic reticulum for proteasomal degradation via the ER-associated degradation (ERAD) pathway
Autophagosome-lysosome fusion: VCP facilitates the recruitment of autophagic machinery to damaged organelles and protein aggregates
DNA repair: VCP regulates DNA double-strand break repair through histone ubiquitination and repair factor recruitment
VCP inhibition enhances autophagic flux by promoting autophagosome-lysosome fusion. In cells with VCP mutations or in neurodegenerative diseases with impaired autophagy, VCP inhibitors restore the ability of cells to clear toxic protein aggregates including: [@vcp2023]
TDP-43 aggregates in ALS/FTD
[Amyloid-beta](/proteins/amyloid-beta) plaques in Alzheimer's disease
[Alpha-synuclein](/proteins/alpha-synuclein) Lewy bodies in Parkinson's disease
[Huntingtin protein](/proteins/huntingtin) aggregates in Huntington's disease
ERAD Modulation
The ERAD pathway is crucial for degrading misfolded proteins from the endoplasmic reticulum. VCP inhibitors modulate ERAD activity, reducing the accumulation of toxic ER stress species that trigger apoptotic pathways in [neurons](/entities/neurons). [@erad2020]
Preclinical Evidence
VCP-Associated Inclusion Body Myopathy
In preclinical models of VCP-associated inclusion body myopathy (IBM), VCP inhibitors demonstrate: [@vcpassociated2021]
Reduced cytoplasmic TDP-43 inclusions in muscle cells
Improved mitochondrial function and reduced [ROS](/entities/reactive-oxygen-species) production
Decreased muscle fiber degeneration
Enhanced autophagic clearance of mutant VCP aggregates
ALS/FTD Models
In cellular and animal models of ALS and FTD: [@tdp2022]
VCP knockdown or inhibition reduces TDP-43 aggregation
VCP inhibitors improve survival of motor neurons in vitro
In TDP-43 transgenic mice, VCP inhibition decreases TDP-43 pathology and improves behavioral outcomes
Combination approaches with autophagy inducers show synergistic benefits
Amyotrophic Lateral Sclerosis
Multiple studies support VCP as a therapeutic target in ALS: [@vcp2023a]
VCP mutations are found in familial ALS cases
TDP-43 pathology in ALS involves VCP-mediated degradation pathways
VCP inhibitors reduce excitotoxicity-induced motor neuron death
Preclinical studies show improved neuromuscular function in ALS models
Clinical Trial Status
CDK5 Inhibitors with VCP Activity
Cyclin-dependent kinase 5 (CDK5) phosphorylates VCP and modulates its activity. [CDK5](/genes/cdk5) inhibitors with VCP-modulating properties are in development: [@cdk2021]
Roscovitine (Seliciclib): Multi-CDK inhibitor that indirectly modulates VCP activity; completed Phase II trials for ALS with modest efficacy signals
AT7519: [CDK5](/proteins/cdk5)/2/9 inhibitor in preclinical development for neurodegenerative diseases
Small Molecule VCP Inhibitors
Direct VCP inhibitors are in various stages of development: [@small2022]
DBeQ: Early-stage VCP inhibitor demonstrating proof-of-concept in cellular models
NMS-873: Potent VCP allosteric inhibitor showing efficacy in ALS/FTD models
CB-5083: Clinical-stage VCP inhibitor (oncology); repurposing potential for neurodegeneration
Clinical Considerations
Current clinical development focuses on: [@clinical2023]
[Autophagy Inducers in Neurodegeneration](/therapeutics/autophagy-inducers-neurodegeneration) — Complementary approach
Future Directions
VCP-targeted therapy represents a promising approach for neurodegenerative diseases characterized by impaired protein homeostasis. Key priorities include: [@future2024]
Developing brain-penetrant VCP inhibitors with optimal pharmacokinetics
Identifying biomarkers for patient selection and treatment response
Exploring combination therapies with autophagy modulators and anti-aggregation compounds
Advancing clinical trials in genetically-defined patient populations
See Also
VCP Protein (p97) - Valosin-Containing Protein
[Inclusion Body Myopathy with Paget Disease of Bone and Frontotemporal Dementia (IBMPFD)](/diseases/frontotemporal-disease)
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