Regulation of transcription in huntington's disease

Huntington's disease (HD) is caused by the inheritance of a copy of the huntingtin gene that has a specific mutation. People who inherit a mutated huntingtin gene will develop debilitating symptoms that include loss of coordinated movement, loss of mental function and psychiatric problems. Some people live several decades before symptoms interfere with their day-to-day activities but in all cases symptoms worsen and inevitably lead to death. To date, there is no effective treatment to improve symptoms or slow the disease. The genetic defect in huntingtin was described over a decade ago, but we still do not know how mutant huntingtin causes brain cells to dysfunction and eventually die. We do know that mutant huntingtin has a function that is different than the normal protein and that it causes a number of changes in cells including the build up of protein aggregates in the nucleus of neurons and changes in the levels of messager RNAs (mRNAs) necessary for neurons to function. The goal of the current research is to determine how the expression of mutant huntingtin leads to lower steady-state levels of these specific mRNAs in transgenic mouse models of HD and in cell culture models. Our hypothesis is that mutant huntingtin protein binds to proteins that are specifically expressed in the area of the brain that is most vulnerable to the effect of mutant huntingtin and prevents these protein factors from controlling normal gene expression. An understanding of the mechanism whereby mutant huntingtin causes its deleterious effects may indicate potential therapeutic targets for the treatment of HD and will allow us to understand the very basis of the development of HD.