Mar 18, 2020

Lipid metabolic stress in development defines which genetically-susceptible DYT-TOR1A mice develop disease

bioRxiv
Ana CascalhoRose E Goodchild

Abstract

There has been enormous progress defining the genetic landscape of disease. However, genotypes rarely fully predict neurological phenotypes, and we rarely understand why. TOR1A +/Δgag that causes dystonia with ~30% penetrance is a classic case. Here we show, in inbred mice, that +/Δgag affects embryonic brain lipid metabolism with sex-skewed reduced penetrance. Penetrance is affected by environmental context, including maternal diet. The lipid metabolic defect resolves during post-natal development. Nevertheless, we discover dystonia-like symptoms in ~30% of juvenile female Tor1a+/Δgag mice, and prevent these symptoms by genetically suppressing abnormal lipid metabolism. We conclude that Tor1a+/Δgag embryos poorly buffer metabolic stress in utero, resulting in a period of abnormal metabolism that hardwires the brain for dystonia in later life. The data show unexpected and profound impacts of sex, and thus highlight the importance of examining male and female animal models of disease.

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Mentioned in this Paper

Dyt1 protein, mouse
Landscapes
Lipids
Dystonia Disorders
Metabolic Stress Response
Brain
Lipid Metabolism
Metabolism
TOR1A protein, human
Laboratory mice

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