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

Authors: Eschbach, Judith  Fergani, Anissa  Oudart, Hugues  Robin, Jean-Patrice  Rene, Frédérique  Gonzalez de Aguilar, Jose-Luis  Larmet, Yves  Zoll, Joffrey  Hafezparast, Majid  Schwalenstocker, Birgit  Loeffler, Jean-Philippe  Ludolph, Albert C  Dupuis, Luc 
Citation: Eschbach J, etal., Biochim Biophys Acta. 2011 Jan;1812(1):59-69. doi: 10.1016/j.bbadis.2010.09.009. Epub 2010 Sep 29.
Pubmed: (View Article at PubMed) PMID:20887786
DOI: Full-text: DOI:10.1016/j.bbadis.2010.09.009

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.

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RGD ID: 13673864
Created: 2018-06-23
Species: All species
Last Modified: 2018-06-23
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.