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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.

journal_name

Hum Mol Genet

journal_title

Human molecular genetics

authors

Llewellyn KJ,Nalbandian A,Jung KM,Nguyen C,Avanesian A,Mozaffar T,Piomelli D,Kimonis VE

doi

10.1093/hmg/ddt523

subject

Has Abstract

pub_date

2014-03-01 00:00:00

pages

1333-44

issue

5

eissn

0964-6906

issn

1460-2083

pii

ddt523

journal_volume

23

pub_type

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