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Downregulation of stearoyl‐CoA desaturase in Huntington's disease
Author(s) -
Lingrell Susanne,
Lehner Richard,
Sipione Simonetta
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.707.20
Subject(s) - huntingtin , sterol regulatory element binding protein , neurodegeneration , downregulation and upregulation , huntington's disease , biology , transcription factor , trinucleotide repeat expansion , striatum , huntingtin protein , endocrinology , biochemistry , microbiology and biotechnology , medicine , gene , chemistry , disease , mutant , allele , dopamine
Huntington's disease (HD) is a neurodegenerative disorder characterized by motor, psychiatric and cognitive dysfunction. The disease is caused by the abnormal expansion of a polyglutamine stretch in the N‐terminal region of huntingtin, a ubiquitous protein with unknown function. Mutant huntingtin has been recently shown to interfere with the nuclear localization of the sterol‐regulatory element binding protein (SREBP)‐1, a transcription factor that is key to the expression of enzymes involved in the synthesis of fatty acids. THE OBJECTIVE of this work was to assess whether dysregulation of SREBP‐1 activity affects fatty acid metabolism in HD brains. Using real‐time PCR we have found that expression of stearoyl‐CoA desaturase (SCD), the main mammalian desaturase for the production of monounsaturated fatty acids and a major transcriptional target of SREBP‐1, is down‐regulated in cell and animal models of HD. SCD down‐regulation across HD brain regions mirrors the pattern of neurodegeneration in HD, with the striatum displaying the strongest reduction in SCD expression. Reduced expression of SCD in HD brains is likely to result in an altered ratio between saturated and unsaturated fatty acids, with subsequent perturbations in lipid and membrane composition and altered membrane fluidity, thus representing an important determinant of neural dysfunction in HD. This research is supported by the Huntington Society of Canada and the Canadian Institutes of Health Research.