title: Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease.
abstract: Valosin-containing protein (VCP)-associated disease caused by mutations in the VCP gene includes combinations of a phenotypically heterogeneous group of disorders such as hereditary inclusion body myopathy, Paget's disease of bone, frontotemporal dementia and amyotrophic lateral sclerosis. Currently, there are no effective treatments for VCP myopathy or dementia. VCP mouse models carrying the common R155H mutation include several of the features typical of the human disease. In our previous investigation, VCP(R155H/R155H) homozygous mice exhibited progressive weakness and accelerated pathology prior to their early demise. Herein, we report that feeding pregnant VCP(R155H/+) heterozygous dams with a lipid-enriched diet (LED) results in the reversal of the lethal phenotype in VCP(R155H/R155H) homozygous offspring. We examined the effects of this diet on homozygous and wild-type mice from birth until 9 months of age. The LED regimen improved survival, motor activity, muscle pathology and the autophagy cascade. A targeted lipidomic analysis of skeletal muscle and liver revealed elevations in tissue levels of non-esterified palmitic acid and ceramide (d18:1/16:0), two lipotoxic substances, in the homozygous mice. The ability to reverse lethality, increase survival, and ameliorate myopathy and lipids deficits in the VCP(R155H/R155H) homozygous animals suggests that lipid supplementation may be a promising therapeutic strategy for patients with VCP-associated neurodegenerative diseases.
authors.affiliation: Department of Pediatrics, Division of Genetics and Metabolism.
authors.forename: Katrina J
authors.initials: KJ
authors.lastname: Llewellyn
authors.forename: Angèle
authors.initials: A
authors.lastname: Nalbandian
authors.forename: Kwang-Mook
authors.initials: KM
authors.lastname: Jung
authors.forename: Christopher
authors.initials: C
authors.lastname: Nguyen
authors.forename: Agnesa
authors.initials: A
authors.lastname: Avanesian
authors.forename: Tahseen
authors.initials: T
authors.lastname: Mozaffar
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Kimonis
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D000818:Animals; D001343:Autophagy / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D004032:Diet; D004195:Disease Models, Animal; D018450:Disease Progression; D004576:Electromyography; D056726:Genetic Association Studies; D006579:Heterozygote; D006720:Homozygote; D007738:Kyphosis / Q000235:genetics / Q000473:pathology; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D010001:Osteitis Deformans / Q000235:genetics / Q000473:pathology; D000074405:Valosin Containing Protein
chemical_list: D018797:Cell Cycle Proteins; D000251:Adenosine Triphosphatases; C000614178:VCP protein, human; D000074405:Valosin Containing Protein; C000614179:Vcp protein, mouse