The discovery of effective therapies and of disease mechanisms underlying valosin containing protein (VCP)-associated myopathies and neurodegenerative disorders remains elusive. VCP disease, caused by mutations in the VCP gene, are a clinically and genetically heterogeneous group of disorders with manifestations varying from hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia (IBMPFD), and amyotrophic lateral sclerosis (ALS). In the present study, we examined the effects of higher dietary lipid percentages on VCPR155H/R155H, VCPR155H/+ and Wild Type (WT) mice from birth until 15 months of age by immunohistochemical and biochemical assays. Findings illustrated improvement in the muscle strength, histology, and autophagy signaling pathway in the heterozygote mice when fed 9% lipid-enriched diets (LED). However, increasing the LED by 12%, 30%, and 48% showed no improvement in homozygote and heterozygote survival, muscle pathology, lipid accumulation or the autophagy cascade. These findings suggest that a balanced lipid supplementation may have a therapeutic strategy for patients with VCP-associated multisystem proteinopathies.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4489713 | PMC |
| http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131995 | PLOS |
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Provisional practice recommendation for the management of myopathy in VCP-associated multisystem proteinopathy.
Ann Clin Transl Neurol
May 2023
Department of Neurology, University of California-Irvine School of Medicine, Orange, California, USA.
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.
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Orphanet J Rare Dis
July 2022
Division of Genetic and Genomic Medicine, Department of Pediatrics, University of California-Irvine, Lab and FEDEX: Hewitt Hall, Rm 2038, Health Sciences Rd., Irvine, CA, 92697, USA.
Background: Valosin containing protein (VCP) is an important protein with many vital functions mostly related to the ubiquitin-proteasome system that provides protein quality control. VCP-associated inclusion body myopathy with Paget disease of bone and frontotemporal dementia, also termed VCP disease and multisystem proteinopathy (MSP 1), is an autosomal dominant disorder caused by monoallelic variants in the VCP gene on human chromosome 9. VCP has also been strongly involved in cancer, with over-activity of VCP found in several cancers such as prostate, pancreatic, endometrial, esophageal cancers and osteosarcoma.
View Article and Find Full Text PDFVCP suppresses proteopathic seeding in neurons.
Mol Neurodegener
April 2022
Department of Neurology, Hope Center for Neurological Diseases, Washington University School of Medicine, St Louis, MO, 63110, USA.
Article Synopsis
- Neuronal degeneration linked to the spread of misfolded proteins, such as αS, Tau, and TDP-43, is poorly understood, particularly in the context of multisystem proteinopathy (MSP) associated with mutations in the VCP protein.
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- Experiments demonstrated that MSP-associated VCP mutations enhance both αS and TDP-43 seeding in neurons, suggesting that these mutations exacerbate neurodegeneration patterns observed in MSP patients.
Development of a standard of care for patients with valosin-containing protein associated multisystem proteinopathy.
Orphanet J Rare Dis
January 2022
Department of Pediatrics, University of California - Irvine School of Medicine, Orange, CA, USA.
Valosin-containing protein (VCP) associated multisystem proteinopathy (MSP) is a rare inherited disorder that may result in multisystem involvement of varying phenotypes including inclusion body myopathy, Paget's disease of bone (PDB), frontotemporal dementia (FTD), parkinsonism, and amyotrophic lateral sclerosis (ALS), among others. An international multidisciplinary consortium of 40+ experts in neuromuscular disease, dementia, movement disorders, psychology, cardiology, pulmonology, physical therapy, occupational therapy, speech and language pathology, nutrition, genetics, integrative medicine, and endocrinology were convened by the patient advocacy organization, Cure VCP Disease, in December 2020 to develop a standard of care for this heterogeneous and under-diagnosed disease. To achieve this goal, working groups collaborated to generate expert consensus recommendations in 10 key areas: genetic diagnosis, myopathy, FTD, PDB, ALS, Charcot Marie Tooth disease (CMT), parkinsonism, cardiomyopathy, pulmonology, supportive therapies, nutrition and supplements, and mental health.
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J Transl Med
January 2022
Division of Genetics and Genomic Medicine, Dept. of Pediatrics, UC Irvine, Irvine, CA, USA.
Background: Pathogenic gain of function variants in Valosin-containing protein (VCP) cause a unique disease characterized by inclusion body myopathy with early-onset Paget disease of bone and frontotemporal dementia (also known as Multisystem proteinopathy (MSP)). Previous studies in drosophila models of VCP disease indicate treatment with VCP inhibitors mitigates disease pathology. Earlier-generation VCP inhibitors display off-target effects and relatively low therapeutic potency.
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