| Health / Medical Topics |
Inhibition of Huntington's Disease Pathway
Huntington's disease is a neurodegenerative condition caused by a dominant mutation in a gene encoding a protein now called huntingtin. Large polyglutamine repeats in the huntingtin protein are the genetic defect responsible for this condition, caused by expansion of a three-base pair repeat in the gene. Similar expansions of polyglutamine repeats are also found in other genes involved in neurodegenerative conditions. The polyglutamine repeat makes huntingtin protein insoluble and triggers the formation of protein aggregates. There are a few hypotheses for the connection between these aggregates and the neurodegeneration observed in Huntington's disease. One hypothesis is that mutant huntingtin moves into the nucleus and interferes with transcriptional activation involving the transcriptional coactivator CBP (CREB binding protein) and other coactivators. CBP interacts with transcriptional regulatory factors and with the basal transcriptional machinery to help regulate transcription. CBP is a large protein with multiple domains and in addition to interacting with several different transcription factors also has a histone acetylase enzyme activity. Mutant huntingtin binds to CBP, drawing it into insoluble protein aggregates. Mutant huntingtin also interacts directly with the acetyltransferase domain of CBP, blocking this activity. Activation of CBP acetyltransferase activity by transcriptional regulators results in the acetylation of histones in the promoter and enhancer regions of active genes, contributing to transcriptional activation by making these genes more accessible in chromatin. The lack of CBP in Huntington's affected neurons may lead to transcriptional repression of key genes that in turn leads to neurodegeneration. One potential treatment being tested is the treatment of Huntington's affected individuals with histone deacetylase inhibitors to restore normal acetylation levels and transcription. The repression of transcription may also be involved in other neurodegenerative conditions caused by proteins with expansions of polyglutamine repeats. (NCI Thesaurus/BIOCARTA)
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