Our laboratory was the first to identify VCP mutations as a cause of hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis, and has made progress in identifying the underlying molecular pathogenesis of these diseases. Studies of patients'myoblasts and the heterozygous R155H mouse have placed VCP at the intersection of the ubiquitin-proteasome signaling and autophagy pathways, both mechanisms being considered responsible for the intracellular protein degradation and abnormal pathology seen in muscle and brain. We have developed the first knock-in VCP mouse model carrying the common R155H mutation, which has many clinical features typical of the human disease (1). Unlike disease progression in the R155H heterozygous (VCPR155H/+) mouse model, homozygotes (VCPR155H/R155H) have a more severe muscle, brain and spinal cord pathology, with most surviving no more than 21 days. Homozygotes demonstrate an abnormal autophagic pathway and mitochondrial proliferation, as evidenced by structural and functional studies. Recent preliminary studies have shown that feeding pregnant heterozygous dams a diet with a 3% increase in fat results in a dramatic improvement in the survival of their homozygous offspring. These offspring live longer than 21 days and are successfully weaned, demonstrating that an increased fat diet ameliorates the lethal phenotype. In this application, we propose to investigate the optimum percentage of fat content on further rescuing the lethal phenotype. We will also study the important altered mitochondrial, autophagy and ubiquitin-proteasome molecular pathways in the homozygous VCP knock-in mice treated with normal versus high-fat diets. Studying this observation affords the opportunity to develop a promising therapeutic strategy for patients with VCP and related diseases.

Public Health Relevance

The knock-in homozygous VCP R155H knock-in mouse demonstrates more severe disease compared to the heterozygous R155H VCP mouse model and dies by 21 days. The mice have many of the pathological features typical of hereditary inclusion body myopathy, Paget disease of bone, frontotemporal dementia (IBMPFD) and ALS associated with mutations in the VCP gene. We have recently identified that we can rescue the lethal phenotype by feeding pregnant dams and pups a higher fat diet. This proposal offers the opportunity of utilizing the knock-in homozygous mice for the necessary preclinical studies before evaluating this promising treatment in patients with VCP disease.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Nuckolls, Glen H
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University of California Irvine
Schools of Medicine
United States
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Nalbandian, Angèle; Llewellyn, Katrina J; Nguyen, Christopher et al. (2015) Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show promising results in valosin containing protein multisystem proteinopathy. PLoS One 10:e0122888
Llewellyn, Katrina J; Walker, Naomi; Nguyen, Christopher et al. (2015) A Fine Balance of Dietary Lipids Improves Pathology of a Murine Model of VCP-Associated Multisystem Proteinopathy. PLoS One 10:e0131995
Llewellyn, Katrina J; Nalbandian, Angele; Jung, Kwang-Mook et al. (2014) Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. Hum Mol Genet 23:1333-44
Nalbandian, Angèle; Llewellyn, Katrina J; Badadani, Mallikarjun et al. (2013) A progressive translational mouse model of human valosin-containing protein disease: the VCP(R155H/+) mouse. Muscle Nerve 47:260-70
Yin, H Z; Nalbandian, A; Hsu, C-I et al. (2012) Slow development of ALS-like spinal cord pathology in mutant valosin-containing protein gene knock-in mice. Cell Death Dis 3:e374
Nalbandian, Angele; Llewellyn, Katrina J; Kitazawa, Masashi et al. (2012) The homozygote VCP(RýýýýýýýýH/RýýýýýýýýH) mouse model exhibits accelerated human VCP-associated disease pathology. PLoS One 7:e46308