PUBLICATION
Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors
- Authors
- Futter, M., Diekmann, H., Schoenmakers, E., Sadiq, O., Chatterjee, K., and Rubinsztein, D.C.
- ID
- ZDB-PUB-090526-19
- Date
- 2009
- Source
- Journal of Medical Genetics 46(7): 438-446 (Journal)
- Registered Authors
- Diekmann, Heike
- Keywords
- huntingtin, huntington’s disease, nuclear receptors, transcription, liver X receptor
- MeSH Terms
-
- Amino Acid Motifs
- Animals
- COS Cells
- Chlorocebus aethiops
- DNA-Binding Proteins/agonists
- DNA-Binding Proteins/genetics
- DNA-Binding Proteins/metabolism*
- Gene Knockdown Techniques
- Humans
- Mutation*
- Nerve Tissue Proteins/genetics
- Nerve Tissue Proteins/metabolism*
- Nuclear Proteins/genetics
- Nuclear Proteins/metabolism*
- Orphan Nuclear Receptors
- Protein Binding
- Protein Interaction Mapping
- Protein Structure, Tertiary
- Receptors, Cytoplasmic and Nuclear/agonists
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism*
- Transcription, Genetic*
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- PubMed
- 19451134 Full text @ J. Med. Genet.
Citation
Futter, M., Diekmann, H., Schoenmakers, E., Sadiq, O., Chatterjee, K., and Rubinsztein, D.C. (2009) Wild-type but not mutant huntingtin modulates the transcriptional activity of liver X receptors. Journal of Medical Genetics. 46(7):438-446.
Abstract
Huntington's disease is caused by expansion of a polyglutamine tract found in the amino-terminal of the ubiquitously expressed protein huntingtin. Well studied in its mutant form, huntingtin has a wide variety of normal functions, loss of which may also contribute to disease progression. Widespread transcriptional dysfunction occurs in brains of huntington's disease patients and in transgenic mouse and cell models of huntington's disease. To identify new transcriptional pathways altered by the normal and/or abnormal function of huntingtin, we probed several nuclear receptors, normally expressed in the brain, for binding to huntingtin in its mutant and wild-type forms. Wild-type huntingtin could bind to a number of nuclear receptors; LXRalpha, PPARgamma, VDR and TRalpha1. Over-expression of huntingtin activated, whilst knockout of huntingtin decreased, LXR-mediated transcription of a reporter gene. Loss of huntingtin also decreased expression of the LXR target gene, ABCA1. In vivo, huntingtin-deficient zebrafish had a severe phenotype and reduced expression of LXR regulated genes. An LXR agonist was able to partially rescue the phenotype and the expression of LXR target genes in huntingtin-deficient zebrafish during early development. Our data suggest a novel function for wild-type huntingtin as a co-factor of LXR. However, this activity is lost by mutant huntingtin that only interacts weakly with LXR.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping