Several lines of evidence suggest that mutant huntingtin affects gene transcription by sequestering transcription activating and repressing proteins. This does not explain the gene expression changes that occur before mutant huntingtin is detectable in the nucleus, nor does it account for transcription changes caused by abnormal signaling from damaged afferent neurons. The overall aim of this application is to test the hypothesis that the earliest gene expression changes in Huntington's disease (HD) reflect a response of the neuron to misfolded huntingtin protein and to abnormal signaling between afferent and target neurons. To accomplish this the investigator proposes two Specific Aims 1) use mice and cell culture models that express mutant huntingtin protein in eitherthe nucleus orthe cytoplasm to determine how cells transcriptionally respond to each and 2) use mice that express mutant huntingtin protein in eitherafferent neurons ortarget neurons to determine transcriptional responses in neurons. The transcriptional responses will be correlated with pathogenic changes that occur in response to the transgenes. This will generate information and tools needed to further model and test early processes in Huntington's disease. Our long-term goal is to identify early pathogenic events in Huntington's disease in order to provide rational targets for the development of prophylactic drugs.
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