The goal of this project is to elucidate the function of huntingtin protein, mutation of which underlies Huntington's disease (HD). These mutations are expansions of a polyglutamine repeat motif (coded by CAG trinucleotide repeats in the mRNA) within the protein, making HD one of several known """"""""glutamine repeat disorders"""""""". In this group of neurodegenerative diseases, an expansion of a polyglutamine repeat in a number of different proteins confers the various disease phenotypes. However, in spite of the relatively restricted patterns of differential cell death in HD and the other disorders, the gene products are widely distributed in both central nervous system and peripheral tissues, and both their normal functions and mechanisms of disease are largely unknown. Transcriptional dysregulation and loss of function of transcriptional co-activator proteins have been implicated in the pathogenesis of these diseases. Gene expression arrays on DNA microchips have recently been used to examine the scope of transcriptional changes in transgenic HD mice. The results showed that the genes whose expression levels were altered were part of several different molecular systems, suggesting that mutant huntingtin may affect common transcriptional mechanisms. Our preliminary data demonstrates that mutant huntingtin interacts with components of TFIID complex to inhibit transcription of target genes. In this work we will use cultured striatal cells and transgenic HD mice and postmortem human HD brain samples to identify mechanisms by which mutant huntingtin could trigger neuronal cell death by interfering with the function of TFIID. We will characterize the pathways leading to tissue-restricted transcriptional dysregulation in HD, focusing on the earliest changes in gene expression triggered by mutant huntingtin. Completion of these aims should reveal new insights into general mechanisms of polyglutamine-induced neurodegeneration and lead to identification of new molecular targets for therapies in HD.
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|Savas, Jeffrey N; Makusky, Anthony; Ottosen, Soren et al. (2008) Huntington's disease protein contributes to RNA-mediated gene silencing through association with Argonaute and P bodies. Proc Natl Acad Sci U S A 105:10820-5|
|Cui, Libin; Jeong, Hyunkyung; Borovecki, Fran et al. (2006) Transcriptional repression of PGC-1alpha by mutant huntingtin leads to mitochondrial dysfunction and neurodegeneration. Cell 127:59-69|
|Weydt, Patrick; Pineda, Victor V; Torrence, Anne E et al. (2006) Thermoregulatory and metabolic defects in Huntington's disease transgenic mice implicate PGC-1alpha in Huntington's disease neurodegeneration. Cell Metab 4:349-62|
|Zhai, Weiguo; Jeong, Hyunkyung; Cui, Libin et al. (2005) In vitro analysis of huntingtin-mediated transcriptional repression reveals multiple transcription factor targets. Cell 123:1241-53|