Mutations in cytoplasmic dynein lead to a Huntington's disease-like defect in energy metabolism of brown and white adipose tissues

Eschbach, Judith, Fergani, Anissa, Oudart, Hugues, Robin, Jean-Patrice, Rene, Frédérique, de Aguilar, Jose-Luis Gonzalez, Larment, Yves, Zoll, Joffrey, Hafezparast, Majid, Schwalenstocker, Birgit, Loeffler, Jean-Philippe, Ludolph, Albert C and Dupuis, Luc (2011) Mutations in cytoplasmic dynein lead to a Huntington's disease-like defect in energy metabolism of brown and white adipose tissues. BBA - Molecular Basis of Disease, 1812 (1). pp. 59-69. ISSN 0925-4439

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Abstract

The molecular motor dynein is regulated by the huntingtin protein, and Huntington's disease (HD) mutations of huntingtin disrupt dynein motor activity. Besides abnormalities in the central nervous system, HD animal models develop prominent peripheral pathology, with defective brown tissue thermogenesis and dysfunctional white adipocytes, but whether this peripheral phenotype is recapitulated by dynein dysfunction is unknown. Here, we observed prominently increased adiposity in mice harboring the legs at odd angles (Loa/+) or the Cramping mutations (Cra/+) in the dynein heavy chain gene. In Cra/+ mice, hyperadiposity occurred in the absence of energy imbalance and was the result of impaired norepinephrine-stimulated lipolysis. A similar phenotype was observed in 3T3L1 adipocytes upon chemical inhibition of dynein showing that loss of functional dynein leads to impairment of lipolysis. Ex vivo, dynein mutant adipose tissue displayed increased reactive oxygen species production that was, at least partially, responsible for the decreased cellular responses to norepinephrine and subsequent defect in stimulated lipolysis. Dynein mutation also affected norepinephrine efficacy to elicit a thermogenic response and led to morphological abnormalities in brown adipose tissue and cold intolerance in dynein mutant mice. Interestingly, protein levels of huntingtin were decreased in dynein mutant adipose tissue. Collectively, our results provide genetic evidence that dynein plays a key role in lipid metabolism and thermogenesis through a modulation of oxidative stress elicited by norepinephrine. This peripheral phenotype of dynein mutant mice is similar to that observed in various animal models of HD, lending further support for a functional link between huntingtin and dynein.

Item Type: Article
Schools and Departments: School of Life Sciences > Neuroscience
Subjects: Q Science
Depositing User: EPrints Services
Date Deposited: 06 Feb 2012 20:46
Last Modified: 05 Oct 2012 07:38
URI: http://sro.sussex.ac.uk/id/eprint/28006
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