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VCP-Associated Multisystem Proteinopathy

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of VCP-Associated Multisystem Proteinopathy. Core disease mechanisms, molecul...

2026-04-22
Asta MONDO:0008178 Model: Asta Scientific Corpus Retrieval 17 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of VCP-Associated Multisystem Proteinopathy. Core disease mechanisms, molecul...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 17
  • Snippets retrieved: 20

Relevant Papers

[1] Multisystem Proteinopathy Due to VCP Mutations: A Review of Clinical Heterogeneity and Genetic Diagnosis

  • Authors: G. Pfeffer, Grace Lee, Carly S. Pontifex, R. Fanganiello, Alli Peck et al.
  • Year: 2022
  • Venue: Genes
  • URL: https://www.semanticscholar.org/paper/ef7c859fe61dbd159535b4474f24530fcfc8aa16
  • DOI: 10.3390/genes13060963
  • PMID: 35741724
  • PMCID: 9222868
  • Citations: 48
  • Influential citations: 2
  • Summary: Clinical features and genetic diagnosis of diseases caused by mutations in the gene encoding valosin-containing protein (VCP/p97), the functionally diverse AAA-ATPase, and genetic counselling implications of VCP-MSP are reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.653) > Valosin-containing protein (VCP) is encoded by VCP on chromosome 9 and it is implicated in numerous human disease phenotypes with autosomal dominant inheritance. VCP is a highly conserved, ubiquitously and abundantly expressed ATPase. Indeed, VCP may make up as much as 1% of all cytoplasmic protein [1]. VCP mediates ubiquitindependent cellular processes through the ubiquitin-proteasome system (UPS) [2], protein quality control [3,4], transcription factor processing [5], membrane fusion [6], cell cycle control [7], and regulation of autophagy [8,9]. > Over 50 heterozygous missense mutations in VCP have been identified in patients with multisystem proteinopathy 1 (MSP1), an autosomal dominant, adult-onset progressive disorder, also known as inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia (IBMPFD), or VCP disease (hereafter referred to as VCP-MSP) [10,11]. The major pathological feature seen in VCP-MSP is the presence of ubiquitin-positive protein aggregates in muscle tissues of patients affected by inclusion body myopathy (IBM). Intranuclear TDP-43+ inclusions are demonstrated in patients with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) [12]. In Paget disease of bone (PDB), abnormally large osteoclasts containing nuclear inclusions resemble the muscle pathology findings [13]. On the whole, the pathological findings of VCP-MSP suggest that abnormal protein clearance is the major molecular mechanism affected by VCP mutations causing human disease. In other forms of MSP (recently reviewed) [11], it has also been suggested that the common molecular mechanism relates to the disruption of two major protein clearance pathways: the UPS and autophagy [14]. However, future studies may identify others among VCP's diverse molecular mechanisms that are relevant to MSP and other human diseases.

[2] Case report of a family with hereditary inclusion body myopathy with VCP gene variant and literature review

  • Authors: Greta Asadauskaitė, R. Vilimienė, Vytautas Augustinavičius, B. Burnytė
  • Year: 2023
  • Venue: Frontiers in Neurology
  • URL: https://www.semanticscholar.org/paper/57911ba9ebb9eae5a498b4bea89b4667532433f0
  • DOI: 10.3389/fneur.2023.1290960
  • PMID: 38146440
  • PMCID: 10749511
  • Summary: A family with myopathy due to c.277C > T variant in VCP gene is presented, which experienced muscle wasting and weakness in the proximal and distal parts of the limbs which is a common finding in VCP related disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.631) > Valosin-containing protein (VCP) related disease is a rare, autosomal dominant, multisystem proteinopathy characterized by inclusion body myopathy (IBM), Paget disease of bone (PDB) and frontotemporal dementia (FTD), affecting around 90%, 28-42%, and 14-30% of patients accordingly (1,2). Other manifestations include amyotrophic lateral sclerosis (ALS), Alzheimer's disease, Parkinson's disease, Charcot-Marie-Tooth type 2 disease and complex hereditary spastic paraplegia (3)(4)(5)(6). VCP related disease has been associated with heterozygous missense variants in VCP gene. VCP belongs to the ATPases associated with diverse cellular Activities (AAA+) family, which uses ATP for protein remodeling. Each subunit contains N-terminal binding domain and two ATPase domains, D1 and D2 (7,8). VCP is involved in a variety of cellular activities such as cell cycle control, organelle biogenesis and elimination, cellular signaling, membrane fusion, transcription, regulation of autophagy and protein degradation (8,9). Missense variants at the NTD-D1 interface of the VCP are thought to cause a disruption in protein homeostasis causing a spectrum of progressive degenerative diseases (7,10,11). > In this paper we report patient and his father with c.277C > T [p.(Arg93Cys)] variant in VCP gene, presenting with IBM. Patient's and his father's phenotype is compared with phenotypes reported in literature.

[3] FYCO1 Increase and Effect of Arimoclomol–Treatment in Human VCP–Pathology

  • Authors: A. Güttsches, N. Meyer, R. Zahedi, T. Evangelista, Thomas Muentefering et al.
  • Year: 2022
  • Venue: Biomedicines
  • URL: https://www.semanticscholar.org/paper/a20d34a1663de907a58a0d7ab8224ad894cd6fce
  • DOI: 10.3390/biomedicines10102443
  • PMID: 36289705
  • PMCID: 9598455
  • Citations: 2
  • Summary: The combined results of this study reveal a dysregulation of FYCO1 in the context of VCP–etiopathology, highlight arimoclomol as a potential drug and introduce proteins targeted by the pre–clinical testing of this drug in fibroblasts.
  • Evidence snippets:
  • Snippet 1 (score: 0.620) > Valosin-containing-protein (VCP) is ubiquitously expressed in human tissues and contributes to different cellular functions including modulation of autophagy, maturation of autophagosomes, control of the ubiquitin-proteasome system (UPS), and endocytosis [1,2]. In the context of modulation of apoptosis and autophagy, VCP has also been linked to the regulation of cellular survival [2]. > Disorders associated with genetic defects of VCP are characterized by a considerable phenotypic variability [3,4], which might accord with the functional spectrum of the corresponding protein. Thus, due to its numerous cellular functions, the clinical presentation of pathogenic variants is complex and may involve several tissues such as skeletal muscle, neurons or bones. However, VCP-associated disorders are rare, which in combination with the great variety of clinical presentations complicates a correct and rapid diagnosis [3]: The most frequent VCP-associated disorder is inclusion body myopathy (IBM) associated with Paget's disease of the bone (PDB) and frontotemporal dementia (FTD), a symptomatic trio leading to the term IBMPFD [4][5][6][7]. Moreover, other neurological manifestations like amyotrophic lateral sclerosis (ALS) [8], progressive spastic paraplegia [9], distal myopathy [10], facio-scapulo-humeral weakness [11], parkinsonism [6], Charcot-Marie-Tooth disease [12] and Huntington's disease [13] have been described in association with pathogenic VCPvariants. Due to the numerous tissues involved and the diverse clinical presentations associated with VCP-related disorders, the term "multisystem proteinopathy (MSP)" has recently emerged to summarize, among others, disorders associated with pathogenic variants affecting the VCP-gene [14]. > Notably, detailed analysis of skeletal muscle tissue derived from patients with sporadic inclusion body myositis (sIBM) revealed an overlap of pathophysiological processes with VCP-associated MSP.

[4] Cardiomyopathy in valosin-containing protein multisystem proteinopathy: Evaluation, diagnosis, and management

  • Authors: Joshua Chan, C.N. Romano, Andy Y. Lee, Stephani Wang, Dawn Lombardo et al.
  • Year: 2025
  • Venue: American Heart Journal Plus: Cardiology Research and Practice
  • URL: https://www.semanticscholar.org/paper/9e8956397d4e421d280fd0cee3ac79938ef97889
  • DOI: 10.1016/j.ahjo.2025.100644
  • PMID: 41234489
  • PMCID: 12607093
  • Summary: Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.
  • Evidence snippets:
  • Snippet 1 (score: 0.609) > Valosin-containing protein (VCP)-associated multisystem proteinopathy is a rare, autosomal dominant disease that affects skeletal muscle, bone, central nervous system, and the heart. While VCP mutations are well established as causing inclusion body myopathy, Paget's disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis, their role in cardiomyopathy remains underrecognized. This review aims to evaluate the pathophysiology, diagnostic approach, and management of VCP-associated cardiomyopathy to provide a framework for clinical care and future research. Emerging evidence from animal models and human case studies suggests that VCP dysfunction disrupts cardiomyocyte homeostasis, impairs protein degradation, and alters mitochondrial function, leading to maladaptive cardiac remodeling and susceptibility to dilated or hypertrophic cardiomyopathy. Echocardiographic studies in patients with VCP variants reveal a significant prevalence of diastolic dysfunction, conduction abnormalities, and variable degrees of systolic impairment. Despite these findings, there are no standardized guidelines for the diagnosis and management of VCP-associated cardiomyopathy. Current treatment strategies are extrapolated from heart failure guidelines, incorporating neurohormonal blockades with angiotensin-converting enzyme inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. Our review highlights the need for systematic screening protocols, genotype-phenotype correlation studies, and the development of targeted therapies. Future research should focus on identifying biomarkers for early detection, elucidating the molecular mechanisms underlying cardiac dysfunction, and assessing the efficacy of novel treatment strategies. Recognizing VCP-associated cardiomyopathy as a distinct clinical entity will facilitate earlier diagnosis, improve patient outcomes, pave the way for disease-specific therapeutic interventions and insights into the mechanism for isolated cardiomyopathy.
  • Snippet 2 (score: 0.534) > Advancements in understanding the role of VCP in the pathogenesis of MSP1 are promising for developing clinical trials for targeted therapies. Currently, there are no successful treatments for VCP-related myopathy or neurological manifestations, and the management of cardiomyopathy is similar to the treatment of other non-ischemic Given that VCP is a multisystem proteinopathy caused by a missense gain-of-function variants, novel therapeutic developments have included targeted excision of the pathogenic variant by exon 5 skipping in mice, which would lead to downstream improvements on skeletal muscle, cardiomyocyte, and oligodendrocyte function [35]. The treated mice showed improvements in muscle strength, quadriceps fibers architecture, autophagy signaling pathway, reduced brain pathology, and reduced severity of Paget-like bone changes with efficient mutated exon removal; however, cardiac parameters were not assessed in this study [11]. > The specific pathophysiologic mechanisms underlying cardiac dysfunction in patients with VCP disease remains poorly understood, but emerging data in mouse models have resulted in further understanding of the role of VCP in cardiomyocytes and heart failure, as reviewed in this manuscript. VCP may have a primary role in cardiomyocyte survival through multiple mechanisms, including protein homeostasis, mitochondrial respiratory function, and elevated production of iNOS and subsequently nitric oxide, which is known to have a cardioprotective effect [36]. Pathogenic variants in VCP are associated with mitochondrial dysfunction, impaired mitophagy, and disrupted energy metabolism, all of which increase cardiomyocyte susceptibility to stress, including ischemia/reperfusion injury. These dysfunctions contribute to the accumulation of damaged mitochondria and elevated oxidative stress. Notably, VCP variants linked to early disease onset or earlier loss of ambulation exhibit higher ATPase activity compared to those associated with later onset [37]. While VCP normally protects cardiac tissue by maintaining protein homeostasis, supporting mitochondrial function, and regulating mTORC1 signaling, its pathogenic variants can predispose individuals to cardiac dysfunction.

[5] Clinical Classification of Variants in the Valosin-Containing Protein Gene Associated With Multisystem Proteinopathy

  • Authors: Marianela Schiava, C. Ikenaga, A. Topf, M. Caballero-Ávila, T. Chou et al.
  • Year: 2023
  • Venue: Neurology: Genetics
  • URL: https://www.semanticscholar.org/paper/635305b65c2cd65cd737b4bd22e1a89d0113586f
  • DOI: 10.1212/NXG.0000000000200093
  • PMID: 37588275
  • PMCID: 10427110
  • Citations: 8
  • Summary: Data is provided to support pathogenicity of 14 of 19 novel VCP variants and provides guidance for clinicians in the evaluation of novel variants in the VCP gene.
  • Evidence snippets:
  • Snippet 1 (score: 0.595) > Valosin-containing protein (VCP), or p97, is an hexameric protein from the AAA+ (ATPases Associated with diverse cellular Activities) family involved in the remodeling of molecules using the energy of ATP hydrolysis. 1 VCP is encoded by the VCP gene, a 17-exon gene on chromosome 9.2 Variants in the VCP gene were initially described in patients with inclusion body myopathy, Paget disease of the bone, and frontotemporal dementia (IBMPFD). 2 However, this acronym is insufficient to capture the expanding phenotypic spectrum of VCP patients, and currently, this disease is more accurately considered a member of a group of conditions known as multisystem proteinopathy (MSP). 3,4 [11][12][13][14][15][16][17][18][19] To date, only missense variants have been described in patients with VCP-MSP. 3,7,20 In all cases, the pattern of inheritance is dominant. The mechanism of VCP dysfunction is likely contextdependent because assays studying VCP mutant function in vitro and in vivo support a gain and loss of function mechanism. In vitro, most pathogenic variants have an increase in ATPase activity, what reflects an induced structural change allowing for an increase in ATP accessibility and ADP release. By contrast, cells and animals expressing VCP-MSP variants behave similarly to VCP chemical or genetic inhibition suggesting that VCP pathogenic variants are dysfunctional. 21 How the apparent increase in ATPase activity in vitro correlates with a loss of VCP function in vivo remains to be explored but is likely due to the complex interactions of adaptor proteins mediated by the ATPase cycle. > Challenges in asserting the pathogenicity to novel VCP variants are due to the diverse phenotypic presentations, the possible varied gene penetrance, and the fact that ancillary tests may support the diagnosis but do not show pathognomonic features.

[6] Analysis of muscle magnetic resonance imaging of a large cohort of patient with VCP-mediated disease reveals characteristic features useful for diagnosis

  • Authors: D. Esteller, Marianela Schiava, J. Verdú-Díaz, R. Villar-Quiles, Boris Dibowski et al.
  • Year: 2023
  • Venue: Journal of Neurology
  • URL: https://www.semanticscholar.org/paper/738d7da150cc8815dfda3f1f13fd37ccfba26c8e
  • DOI: 10.1007/s00415-023-11862-4
  • PMID: 37603075
  • PMCID: 10632218
  • Citations: 10
  • Summary: Ten diagnostic characteristics based on the pattern identified that allowed us to distinguish VCP disease from other neuromuscular diseases with high accuracy are identified.
  • Evidence snippets:
  • Snippet 1 (score: 0.585) > The VCP gene encodes the valosin-containing protein (VCP), a member of the ATPases Associated with diverse cellular Activities (AAA +) family of proteins. VCP is Robert Y. Carlier and Jordi Díaz-Manera have equally contributed to this work. > Extended author information available on the last page of the article ubiquitously expressed, and it is involved in protein degradation by the ubiquitin-proteasome system and in cellular homeostasis regulation [1][2][3]. The group of Dr. Kimonis described in 2001 that mutations in the VCP gene were the cause of an autosomal dominant disease characterized by the combination of an inclusion body myopathy (IBM), Paget's disease of the bone (PDB) and frontotemporal dementia (FTD), also known as IBMPFD [4][5][6][7]. Since the original description, many other phenotypes and diseases have been reported associated with mutations in the VCP gene including facio-scapulo-humeral muscle weakness, distal myopathy, amyotrophic lateral sclerosis, parkinsonism, hereditary spastic paraplegia, Charcot-Marie-Tooth disease type 2, Huntington´s disease and cardiomyopathy [8][9][10][11][12][13][14][15][16][17]. Because of this wide range of clinical presentations, the IBMPFD acronym was replaced by the term multisystem proteinopathy (MSP) to encompass all the phenotypes associated with VCP mutations [6]. Other genes have recently been described to also cause MSP including hnRNPA1, SQSTM1, MATR3, TIA1 and OPTN [18,19]. To better understand the variable features of MSP produced by mutations in the VCP gene (VCP-MSP), we collected demographic, clinical, genetic, muscle MRI and muscle biopsy data of 255 patients from different countries included in the "VCP International Study" [20].

[7] Valosin-containing-protein pathogenic variant p.R487H in Parkinson’s disease

  • Authors: Capucine Piat, Owen A. Ross, W. Springer, E. Benarroch, J. Layne Moore et al.
  • Year: 2024
  • Venue: Clinical Parkinsonism & Related Disorders
  • URL: https://www.semanticscholar.org/paper/6589dcbbb4cef0196cf89034ce312afc1e5f8c5e
  • DOI: 10.1016/j.prdoa.2024.100236
  • PMID: 38283104
  • PMCID: 10818073
  • Summary: We describe a 66-year-old woman with Parkinson’s disease, carrying a known pathogenic missense variant in the Valosin-containing-protein (VCP) gene. She responded excellently to L-dopa, had no cognitive or motoneuronal dysfunction. Laboratory analyses and MRI were unremarkable. Genetic testing revealed a heterozygous variant in VCP(NM_007126.5), chr9 (GRCh3 7):g.35060820C > T, c.1460G > A p.Arg487His (p.R487H).
  • Evidence snippets:
  • Snippet 1 (score: 0.581) > Parkinson's disease (PD) is a complex neurodegenerative disorder with ~ 10 % recognized as familial and an increasing number of identified causative, risk-associated genes. Valosin-containing-protein (VCP) gene encodes for VCP/p97, a ubiquitous ATPase from the AAA + family, which functions as a molecular "chaperone" assisting protein degradation via the ubiquitin-proteasome system, autophagy, membrane fusion, transcription activation, and apoptosis (Fig. 1). VCP-variants can induce misfolded protein inclusions that disrupt cellular mechanisms. VCP occurs in nuclear inclusions of Huntington's disease (HD), Lewy-body disease (LBD), Alzheimer's disease (AD), Creutzfeldt-Jacob disease (CJD) and amyotrophic lateral sclerosis (ALS) with dementia. > Over 80 VCP gene-variants are described in different central and peripheral neurological disorders [1]. Heterogenous clinical phenotypes of VCP-variants have been grouped into an entity called VCP-Multisystem-Proteinopathy (VCP-MSP) [2,3]. VCP-MSP is transmitted in an autosomal-dominant pattern, often caused by VCP-missense variants [2]. Physicians identify VCP-MSP when ≥ 2 of the following are present: inclusion-body-myopathy (IBM), Paget's bone disease (PBD), ALS, or frontotemporal-dementia (FTD). > A cohort of 231 patients from 36 VCP variant-harboring families showed 4 % of VCP-MSP patients with parkinsonism in their disease phenotype. Another large study investigated the role of VCP in 768 PD patients, found heterozygous VCP-variants in 1.4 % of the cohort, but no identified pathogenic variants. One case of idiopathic-like, levodoparesponsive PD was reported in a p.R159C-VCP-variant carrier [4].

[8] Valosin Containing Protein (VCP): A Multistep Regulator of Autophagy

  • Authors: V. Ferrari, R. Cristofani, B. Tedesco, V. Crippa, M. Chierichetti et al.
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/4deb5c598926017418f38f68366d46c3d95d4556
  • DOI: 10.3390/ijms23041939
  • PMID: 35216053
  • PMCID: 8878954
  • Citations: 34
  • Influential citations: 1
  • Summary: A better understanding of VCP complexes and mechanisms in regulating autophagy could define the altered mechanisms by which VCP directly or indirectly causes or modulates different human diseases and revealing possible new therapeutic approaches for NDs.
  • Evidence snippets:
  • Snippet 1 (score: 0.570) > Valosin containing protein (VCP) has emerged as a central protein in the regulation of the protein quality control (PQC) system. VCP mutations are causative of multisystem proteinopathies, which include neurodegenerative diseases (NDs), and share various signs of altered proteostasis, mainly associated with autophagy malfunctioning. Autophagy is a complex multistep degradative system essential for the maintenance of cell viability, especially in post-mitotic cells as neurons and differentiated skeletal muscle cells. Interestingly, many studies concerning NDs have focused on autophagy impairment as a pathological mechanism or autophagy activity boosting to rescue the pathological phenotype. The role of VCP in autophagy has been widely debated, but recent findings have defined new mechanisms associated with VCP activity in the regulation of autophagy, showing that VCP is involved in different steps of this pathway. Here we will discuss the multiple activity of VCP in the autophagic pathway underlying its leading role either in physiological or pathological conditions. A better understanding of VCP complexes and mechanisms in regulating autophagy could define the altered mechanisms by which VCP directly or indirectly causes or modulates different human diseases and revealing possible new therapeutic approaches for NDs.
  • Snippet 2 (score: 0.555) > Neurodegenerative diseases (NDs) are heterogeneous, frequently fatal and caused by the loss of neurons in different regions of the central or peripheral nervous system (CNS or PNS, respectively). NDs present very different phenotypes associated with the degeneration of a specific subset of neurons. Nevertheless, several NDs like Alzheimer's disease (AD), Parkinson's disease (PD), tauopathies, amyotrophic lateral sclerosis (ALS), spinal and bulbar muscular atrophy (SBMA), frontotemporal dementia (FTD), and Huntington's disease (HD) share some clinical features and pathological mechanisms, like the presence of protein inclusions and protein quality control (PQC) system impairment. The presence of alterations in proteostasis leads to the inclusion of these NDs in the group of proteinopathies that also includes diseases known as multisystem proteinopathies and myopathies [1,2]. > The PQC system is composed of chaperones and the degradative pathways, namely, the ubiquitin-proteasome system (UPS) and autophagy. Chaperones are proteins that, by cooperating with co-chaperones, are involved in the recognition of unfolded or misfolded proteins. Their role is based on supporting the proper folding of unfolded or misfolded proteins and, when this fails, on enhancing their clearance [3,4]. Valosin containing protein (VCP) is a chaperone-like protein, encoded by the VCP gene in humans, that has various roles in the PQC system being involved both in UPS and autophagy. VCP has a wellestablished role in enhancing misfolded protein degradation through the UPS, whereas VCP functions in autophagy are still not fully defined [5]. Here, we will present an overview of VCP focusing on its functions in regulating and supporting the autophagic flux and the impact that VCP disease mutations have on autophagy. The proper knowledge on VCP activity in this pathway could help in understanding the pathological mechanisms of VCP-related diseases, possibly opening new therapeutic approaches in proteinopathies.

[9] Muscle Biopsy Findings in Valosin-Containing Protein Multisystem Proteinopathy

  • Authors: Marianela Schiava, Yolande Parkhurst, Matthew Henderson, T. Polvikoski, M. Valtcheva et al.
  • Year: 2025
  • Venue: Neurology: Genetics
  • URL: https://www.semanticscholar.org/paper/ac300232f15e21815cc594850fe65262eb43f65e
  • DOI: 10.1212/NXG.0000000000200265
  • PMID: 40678441
  • PMCID: 12270496
  • Citations: 1
  • Summary: VCP-MSP muscle biopsies consistently show myopathic or mixed patterns with rimmed vacuoles and p62/VCP-positive inclusions, regardless of clinical phenotype, age, or progression, according to this study.
  • Evidence snippets:
  • Snippet 1 (score: 0.565) > Valosin-containing protein multisystem proteinopathy, hereafter VCP-MSP, is an autosomal dominant genetic condition produced by pathogenic variants in the valosin-containing protein gene (VCP gene). 1 VCP is a member of the AAA-ATPase (ATPases associated with diverse cellular activities protein) family which is involved in the remodeling of molecules using the energy generated by hydrolyzing ATP. 2 VCP is ubiquitously expressed through body tissues representing up to 1% of the cellular proteins. 3 VCP's structure consists of an N-terminal domain that interacts with adapters and cofactors, 2 central D1 and D2 ATPase domains, 2 linker domains (L1 and L2), and a carboxy-terminal domain that also links to some cofactors. 2,4 A VCP monomer assembles into a hexamer with a central cylinder formed by the D1/D2 domains. While the D1 domain is responsible for hexamerization, the D2 domain performs the majority of ATPase activity. 5,6 VCP has a key role in maintaining cell homeostasis participating in protein degradation, autophagy, cell cycle control, and regulation of apoptosis. 2,7 e first patients with VCP-MSP reported developed a combination of symptoms including involvement of the skeletal muscle, in the form of an inclusion body myopathy, 8 Paget disease of the bone (PDB), and frontotemporal dementia (FTD). 9 Since that original report, diverse clinical presentations have been reported. 1][12][13][14][15][16][17][18][19][20][21] It is recognized that there is interindividual and intrafamilial variability in the clinical presentation. 22 Although VCP-MSP was considered to affect only adults, a new phenotype affecting children presenting with cognitive decline has been published, broadening the potential phenotypes even more. 23
  • Snippet 2 (score: 0.540) > Background and Objectives Valosin Containing Protein-associated multisystem proteinopathy (VCP-MSP) is a progressive, autosomal dominant disorder caused by pathogenic variants in the VCP gene, resulting in a heterogeneous clinical presentation. Muscle biopsy findings are characteristic but not pathognomonic. This study aimed to comprehensively analyse VCP-related myopathology and explore correlations with clinical phenotypes, genetic variants, and disease progression. Methods Muscle biopsy images and data were collected retrospectively from adults (≥18 years) with pathogenic or likely pathogenic VCP variants enrolled in the VCP Multicentre International Study. Biopsy data were standardized using the “Common Data Elements for Muscle Biopsy Reporting.” Variations in biopsy findings were analysed by biopsy site, time from disease onset, the four most common VCP variants, and clinical phenotypes. Result A total of 112 muscle biopsies were included. Most individuals were male (66.0%). The mean age at biopsy was 53.3 years (SD 10.0), with a mean disease duration of 6.5 years (SD 4.5). The most frequent VCP variant was c.464G>A (p.Arg155His) (18.8%). The top clinical phenotypes were isolated myopathy (37.5%), myopathy with Paget disease of bone (17.9%), and myopathy with motor neuron involvement (13.4%). The vastus lateralis was the most common biopsy site (34.8%), and 91% were open biopsies. Histopathologic findings included atrophic fibres (87.5%), rimmed vacuoles (72.3%), endomysial fibrosis (58.0%), and protein aggregates (51.8%), primarily p62 (60.3%) and VCP (36.2%). Degeneration niches with fibrofatty replacement and atrophic fibres were seen in 33.3% of biopsies without frequency differences by clinical phenotypes. There were no differences

[10] Valosin-Containing Protein (VCP): A Review of Its Diverse Molecular Functions and Clinical Phenotypes

  • Authors: Carly S. Pontifex, Mashiat Zaman, R. Fanganiello, T. Shutt, G. Pfeffer
  • Year: 2024
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/a0717d977acc61d9c08343d1ac6aed94c33f2138
  • DOI: 10.3390/ijms25115633
  • PMID: 38891822
  • PMCID: 11172259
  • Citations: 14
  • Summary: In this review we examine the functionally diverse ATPase associated with various cellular activities (AAA-ATPase), valosin-containing protein (VCP/p97), its molecular functions, the mutational landscape of VCP and the phenotypic manifestation of VCP disease. VCP is crucial to a multitude of cellular functions including protein quality control, endoplasmic reticulum-associated degradation (ERAD), autophagy, mitophagy, lysophagy, stress granule formation and clearance, DNA replication and mito...
  • Evidence snippets:
  • Snippet 1 (score: 0.563) > Although the major roles of VCP in protein quality control are presumed to be the major mechanisms implicated in MSP, the incredible functional diversity and pleiotropic effects of VCP also imply that other mechanisms may be relevant and require further study.VCP cooperates with the 26S proteasome, the main pathway for protein degradation, to manage the protein quality control system.In the nucleus, VCP regulates cell cycle control and the DNA damage response by coordinating proteins at DNA damage sites.In the cytosol, VCP regulates responses to cellular stress by forming and clearing stress granules, facilitating ERAD, autophagy, mitophagy and lysophagy, and VCP may also be involved in apoptosis.The complexity of VCP's diverse molecular functions is also mirrored by the variability in clinical dysfunction caused by pathogenic variants in VCP.The relationship between specific molecular functions of VCP and the spectrum of clinical presentations remains poorly understood, and, in general, genotype-phenotype correlation is still difficult to demonstrate.Certainly, VCP plays many yet-to-be-identified roles in different cellular systems.Given that the role of VCP extends to so many cellular systems, it makes it difficult to ascertain which dysfunction leads to which clinical phenotype.The majority of MSP cases are related to variants at positions 155 and 159, but the phenotypic variability is extensive, suggesting that other genetic or epigenetic factors and/or environmental factors may interact.To better narrow down a causative mechanism in a given tissue, we advise that, when possible, experiments should include one or two other MSP genes such as SQSTM1 or HNRNPA2B1, as this may help identify common mechanisms of dysfunction in MSP.Studies of large cohorts of patients who have common variants in VCP may allow for the identification of genetic modifiers or other factors that contribute to phenotypic variability.Even though pathogenic variants in VCP typically lead to multisystem disease, in general, the affected systems predictably include certain tissue types (primarily skeletal muscle, the cerebrum, motor neurons and osteoclasts).Even though VCP is ubiquitously expressed and participates in numerous crucial cellular functions, pan-systemic disease is not observed.

[11] Myogenic differentiation of VCP disease-induced pluripotent stem cells: A novel platform for drug discovery

  • Authors: K. Llewellyn, A. Nalbandian, Lan Weiss, I. Chang, Howard Yu et al.
  • Year: 2017
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/8f47d29199964591678cb84f32e4991cd50e833a
  • DOI: 10.1371/journal.pone.0176919
  • PMID: 28575052
  • PMCID: 5456028
  • Citations: 14
  • Influential citations: 1
  • Summary: The differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2) illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.
  • Evidence snippets:
  • Snippet 1 (score: 0.559) > Valosin Containing Protein (VCP) disease is an autosomal dominant multisystem proteinopathy caused by mutations in the VCP gene, and is primarily associated with progressive muscle weakness, including atrophy of the pelvic and shoulder girdle muscles. Currently, no treatments are available and cardiac and respiratory failures can lead to mortality at an early age. VCP is an AAA ATPase multifunction complex protein and mutations in the VCP gene resulting in disrupted autophagic clearance. Due to the rarity of the disease, the myopathic nature of the disorder, ethical and practical considerations, VCP disease muscle biopsies are difficult to obtain. Thus, disease-specific human induced pluripotent stem cells (hiPSCs) now provide a valuable resource for the research owing to their renewable and pluripotent nature. In the present study, we report the differentiation and characterization of a VCP disease-specific hiPSCs into precursors expressing myogenic markers including desmin, myogenic factor 5 (MYF5), myosin and heavy chain 2 (MYH2). VCP disease phenotype is characterized by high expression of TAR DNA Binding Protein-43 (TDP-43), ubiquitin (Ub), Light Chain 3-I/II protein (LC3-I/II), and p62/SQSTM1 (p62) protein indicating disruption of the autophagy cascade. Treatment of hiPSC precursors with autophagy stimulators Rapamycin, Perifosine, or AT101 showed reduction in VCP pathology markers TDP-43, LC3-I/II and p62/SQSTM1. Conversely, autophagy inhibitors chloroquine had no beneficial effect, and Spautin-1 or MHY1485 had modest effects. Our results illustrate that hiPSC technology provide a useful platform for a rapid drug discovery and hence constitutes a bridge between clinical and bench research in VCP and related diseases.

[12] Rapamycin and Chloroquine: The In Vitro and In Vivo Effects of Autophagy-Modifying Drugs Show Promising Results in Valosin Containing Protein Multisystem Proteinopathy

  • Authors: A. Nalbandian, K. Llewellyn, C. Nguyen, P. Yazdi, V. Kimonis
  • Year: 2015
  • Venue: PLoS ONE
  • URL: https://www.semanticscholar.org/paper/dddd5c44fc93a2e37b203ab7d64950df04dadb63
  • DOI: 10.1371/journal.pone.0122888
  • PMID: 25884947
  • PMCID: 4401571
  • Citations: 83
  • Influential citations: 3
  • Summary: Results of administration of rapamycin and chloroquine suggest that VCP disease and related neurodegenerative multisystem proteinopathies can now be included as disorders that can potentially be ameliorated by rapalogs.
  • Evidence snippets:
  • Snippet 1 (score: 0.557) > Currently, intense investigations are underway to determine the underlying cellular and molecular disease mechanisms for the development of effective novel advancements/therapeutics of VCP-associated disease and related neurodegenerative disorders. VCP multisystem proteinopathy (MSP) is a degenerative disease which affects various systems and is involved in a number of cellular functions, most of which are related to autophagy ubiquitin-proteasomedependent proteolysis and mitochondrial degradation [35][36][37][38][39]. VCP is highly conserved in evolution suggesting an essential role for normal cellular functions in both unicellular (yeast) and multi-cellular organisms [40][41][42]. The finding that inhibition of VCP expression promotes apoptosis, suggests that intact VCP is indispensable for normal development and cell survival [43]. Previous studies have confirmed the role of VCP in autophagic degradation of ubiquitinated proteins [33,[44][45][46]. demonstrated mTOR dysfunction and its contribution to vacuolar pathology and weakness in VCP inclusion body myopathy [47]. In this report, we established that rapamycin administration ameliorated the muscle pathology phenotype in the VCP R155H/+ animals, while chloroquine revealed a detrimental effect. Our findings further confirm a link between the autophagy-modifying treatment (rapamycin) and autophagy/cellular homeostasis. Thus, we hypothesize that rapamycin counterbalances the muscle pathology and autophagy signaling transduction pathway via the mTOR cascade and may provide a promising strategy for patients with these debilitating VCP-associated multisystem diseases. > Rapamycin is a mammalian target of rapamycin (mTOR) inhibitor-based drug with multiple uses such as in immunosuppression [48], cell proliferation and autophagy stimulation [49]. mTOR functions as an ATP and amino acid sensor to balance nutrient availability and cell growth. The mechanism of action for rapamycin occurs through binding with the 12 kDa FK506-binding protein which in turn binds and activates mTORC1 (complex 1).

[13] VCP-related myopathy: a case series and a review of literature

  • Authors: Eliana Iannibelli, S. Gibertini, M. Cheli, F. Blàsevich, Andrea Cavaliere et al.
  • Year: 2023
  • Venue: Acta Myologica
  • URL: https://www.semanticscholar.org/paper/cb13eb67fd5adb4fa2b9044135be42c06c03e614
  • DOI: 10.36185/2532-1900-244
  • PMID: 37091525
  • PMCID: 10115396
  • Citations: 7
  • Summary: It is strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement, as occasionally reported in the literature.
  • Evidence snippets:
  • Snippet 1 (score: 0.556) > The valosin-containing protein (VCP), a widely expressed protein, controls the ubiquitin-proteasome system, endolysosomal sorting, and autophagy to maintain cellular proteostasis. Frontotemporal dementia (FTD), inclusion body myopathy, and Paget’s disease of the bone (PDB) are all caused by dominant missense mutations in the VCP gene, which interfere with these mechanisms and cause a multisystem proteinopathy. We describe phenotypic and genetic findings of five patients with four different mutations in VCP gene (NM_007126): c.278G > A (p.R93H), c.463C > T (p.R155C), c.410C > T (p.P137L), c.464G > A (p.R155H), c.410C > T (p.P137L). We analysed the patient’ biopsies, all characterized by a muscular phenotype, and we executed immunofluorescence staining to evaluate the presence of proteins: p62, VCP, desmin, myotilin, TDP-43. Eventually we performed a brief literature review to compare our cases with those already reported. Our report strongly suggest that VCP gene mutations can be related with a predominant skeletal muscle phenotype without any central nervous system involvement, as occasionally reported in the literature. Particularly, our patient with R93H shows only myopathic involvement while this mutation has been described once associated only to Hereditary Spastic Paraplegia. Further study will be necessary to understand such a broad and different clinical spectrum.

[14] Provisional practice recommendation for the management of myopathy in VCP‐associated multisystem proteinopathy

  • Authors: B. Roy, Alli Peck, T. Evangelista, G. Pfeffer, Leo H. Wang et al.
  • Year: 2023
  • Venue: Annals of Clinical and Translational Neurology
  • URL: https://www.semanticscholar.org/paper/911ac001ac886231067b2e2c127b0febfce33711
  • DOI: 10.1002/acn3.51760
  • PMID: 37026610
  • PMCID: 10187720
  • Citations: 8
  • Summary: This working group developed a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe to optimize patient care and help future research initiatives.
  • Evidence snippets:
  • Snippet 1 (score: 0.542) > Valosin‐containing protein (VCP)‐associated multisystem proteinopathy (MSP) is a rare genetic disorder with abnormalities in the autophagy pathway leading to various combinations of myopathy, bone diseases, and neurodegeneration. Ninety percent of patients with VCP‐associated MSP have myopathy, but there is no consensus‐based guideline. The goal of this working group was to develop a best practice set of provisional recommendations for VCP myopathy which can be easily implemented across the globe. As an initiative by Cure VCP Disease Inc., a patient advocacy organization, an online survey was initially conducted to identify the practice gaps in VCP myopathy. All prior published literature on VCP myopathy was reviewed to better understand the different aspects of management of VCP myopathy, and several working group sessions were conducted involving international experts to develop this provisional recommendation. VCP myopathy has a heterogeneous clinical phenotype and should be considered in patients with limb‐girdle muscular dystrophy phenotype, or any myopathy with an autosomal dominant pattern of inheritance. Genetic testing is the only definitive way to diagnose VCP myopathy, and single‐variant testing in the case of a known familial VCP variant, or multi‐gene panel sequencing in undifferentiated cases can be considered. Muscle biopsy is important in cases of diagnostic uncertainty or lack of a definitive pathogenic genetic variant since rimmed vacuoles (present in ~40% cases) are considered a hallmark of VCP myopathy. Electrodiagnostic studies and magnetic resonance imaging can also help rule out disease mimics. Standardized management of VCP myopathy will optimize patient care and help future research initiatives.

[15] The Genetics of Monogenic Frontotemporal Dementia

  • Authors: L. Takada
  • Year: 2015
  • Venue: Dementia & Neuropsychologia
  • URL: https://www.semanticscholar.org/paper/a8e017714edbc33cd7977f6ab00731fb43a7a265
  • DOI: 10.1590/1980-57642015DN93000003
  • PMID: 29213965
  • PMCID: 5619362
  • Citations: 45
  • Influential citations: 2
  • Summary: Since the identification of mutations in MAPT (microtubule-associated protein tau gene) in 1998, over 10 other genes have been associated with FTD spectrum disorders, discussed in this review.
  • Evidence snippets:
  • Snippet 1 (score: 0.539) > Mutations in VCP were discovered in 2004 were found to cause a complex phenotype, which initially included inclusion body myopathy, Paget disease of the bone and bvFTD and consequently it was commonly referred to by the acronym IBMPFD. 86 In 2010 however, a study employing exome sequencing found that mutations in VCP could also cause familial ALS, thus expanding the phenotypes associated with VCP mutations. 87 Other reports subsequently suggested that these families could occasionally present systemic manifestations such as heart, liver, peripheral nervous system involvement, among others, and therefore the acronym originally used was no longer deemed adequate. Hence, Benatar et al. proposed that this group of phenotypes be renamed "Multisystem proteinopathy" (MSP). 13 utations in VCP are the most frequent cause of MSP, but mutations in HNRNPA1 and HNRNPA2B1 were also recently identified. 88 Mutations in the SQSTM1 gene have not been associated with inclusion body myopathy, but have since been found in other phenotypes of MSP. 89 Other MSP-causing genes will likely be identified in the future, since mutations in these four genes cannot explain all cases of familial MSP. Takada LT VCP gene. The VCP gene (valosin containing protein) is located on chromosome 9p13.3. The valosin-containing protein is an AAA + protein (ATPase associated with a variety of cellular activities), which participates in multiple cellular processes, such as degradation of ubiquitinated proteins by the ubiquitin-proteasome system and autophagy. 86 here are currently 18 known missense mutations of the gene. 15 Mutations in VCP seem to affect the protein degradation pathways, which can lead to neurodegeneration. 86 ransmission occurs in autosomal dominant pattern of inheritance, with variable penetrance depending on the phenotype (around 30% of patients develop bvFTD, 85-90% develop inclusion body myopathy, and 45-50% have Paget's disease). 90

[16] Hereditary inclusion body myopathy: a clinical and genetic review

  • Authors: Paulo Victor Sgobbi de Souza, Bruno Mattos Lombardi Badia, Eduardo Augusto Gonçalves, I. Farias, Wladimir Bocca Vieira de Rezende Pinto et al.
  • Year: 2020
  • Venue: Revista Neurociências
  • URL: https://www.semanticscholar.org/paper/e691ec98c1b0a097b46584e12dc68cc3c5fa3dcf
  • DOI: 10.34024/rnc.2020.v28.10569
  • Citations: 3
  • Summary: A wide review regarding the main clinical, imaging, pathophysiological, genetic and therapeutic aspects related to hereditary myopathies linked to seven different clinical and genetic presentations linked to at least 7 distinct clinic and genetic monogenic forms.
  • Evidence snippets:
  • Snippet 1 (score: 0.534) > There is marked pathophysiological overlap between genetic mechanisms common to hIBM subtypes and familial ALS involving multisystem proteinopathies and intracytoplasmic system of ubiquitin-proteosome networks 16,27,28 . Thereby, VCP gene mutations result from complex dysfunctions in the biogenesis of the Golgi apparatus, ubiquitin-proteosome system, protein degradation of external mitochondrial membrane, establishment and maturation of the autophagosome, clathrin-mediated membrane endocytosis and cell cycle regulation 29 . > Dysfunctions involving the ribonucleoproteins A1 and B1 originate intracellular defects related to splicing and processing of messenger preRNA and interaction with RNA polymerase II 29 , being, thus, a pathophysiological mechanism not restricted to skeletal muscle groups or to the central nervous system. Regarding other hIBM subtypes, it has not been well-defined if mutations in the gene coding heavy myosin chain IIa could be associated with nonmyopathic complex neurodegenerative spectrum of disorders or with multisystem proteinopathy phenotype 15 . > This complex multisystem disorders have also been linked to other genes involved with similar pathophysiological mechanisms, including OPTN, DNAJB6 and HNRNPDL, thus, disclosing a complex network of proteins involved in intracellular protein homeostasis and related with the same mechanisms previously described in ALS, FTLD and other degenerative disorders 3,27,29,30 . > There is a lot of expectancy that the knowledge related to hIBM etiopathogenesis can represent the basis to understand properly the mechanisms of IBM and other clinically significant neuromuscular and neurodegenerative disorders (including ALS, parkinsonian syndromes and frontotemporal lobar degeneration) and systemic diseases (such as Paget disease of bone), as well as the foundation in the development of common specific therapeutic modalities for such multisystem disorders 29,30 .

[17] Parkinson's Disease: The Dirty Truth about the Air

  • Authors: F. Scorza, A. G. de Almeida, C. Scorza, J. Finsterer
  • Year: 2023
  • Venue: Annals of Indian Academy of Neurology
  • URL: https://www.semanticscholar.org/paper/bbb6681e7f5acc316257ee68270a94c1b578f0e7
  • DOI: 10.4103/aian.aian_839_22
  • PMID: 37034044
  • PMCID: 10081543
  • Summary: The use of three‐dimensional anatomical patient‐specific printed models in surgical clipping of intracranial aneurysm: A pilot study and application of 3D‐printed craniocerebral model in simulated surgery for complex intrACranial lesions.
  • Evidence snippets:
  • Snippet 1 (score: 0.533) > Dear Editor, We report the first case of multisystem proteinopathy (MSP) from India and document an uncommon phenotypic expression. Our patient had pathogenic variants in the valosin-containing protein (VCP) gene. Clinically, there was a peculiar combination of rapidly progressive amyotrophic lateral sclerosis and atypical parkinsonism along with Paget's disease of the bone. There was no evidence of myopathy. The disease seems uncommon in Asia and has been documented sparsely. The term "multisystem proteinopathy (MSP)" applies to a composite of rare inherited disorders affecting muscle, bone, and nervous systems in different combinations. The usual inheritance pattern is autosomal dominant and rarely sporadic. The earliest descriptions of VCP-related diseases were given by Kimonis et al. [1] and Watts et al. [2] They first reported the peculiar combination of hereditary inclusion body myopathy (h-IBM), Paget's disease of bone (PDB), and dementia (FTD), which then came to be recognized as the classical phenotype of the disease known as IBMPFD. Thereafter, the disease has been increasingly reported, largely in Western countries. The term MSP currently incorporates various phenotypic aspects. [3] The major phenotypes known within the spectrum are myopathy, PDB, FTD-ALS, Parkinson's disease, and peripheral neuropathy. Apart from the VCP, other genes now included in the spectrum are heterogeneous nuclear ribonucleoprotein A2B1 and A1 (hnRNPA2B1 and hnRNPA1) genes, Sequestosome 1 (SQSTM1), Matrin-3 (MATR3), T-cell restricted intracellular antigen 1 (TIA1), and optineurin (OPTN). [4,5] The common underlying molecular mechanism is that of disruption of the cellular protein degradation pathways resulting in protein misfolding and aggregation. [4] 47-year female presented with limb-girdle weakness along with neck flexor weakness and dysphagia progressive for six months.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.