Cell Signaling Dysregulation in Huntington's Disease

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Huntington’s disease (HD) is a devastating neurodegenerative disease (ND) that affects approximately 30,000 patients in United States and for which no therapies are available. HD is characterized by massive protein aggregation, preferentially affecting medium spiny neurons (MSNs) in the striatum. Despite numerous studies addressing the importance of MSN degeneration in HD pathology, very little is known about the molecular mechanisms by which mutant huntingtin (mHTT) protein induces MSN death in HD. Recent evidence demonstrated that the essential heat shock transcription factor 1 (HSF1), responsible for the expression of stress protective proteins, is inappropriately degraded in MSNs in HD. We hypothesize that HSF1 degradation is a key pathway involved in MSN dysfunction and loss in HD and preventing its degradation may constitute a potential therapeutic approach. The goal of this proposal is to characterize the mechanism that leads to HSF1 degradation in MSNs, and determine if reversal of this process, even after onset of HD symptoms leads to improved outcomes. In Aim 1 we will test the hypothesis that inappropriate accumulation of the protein p53 in MSNs controls the expression of components of the HSF1 degradation pathway (protein kinase CK2α’ and E3 ligase Fbxw7), ultimately leading to loss of HSF1 and HD symptomology. This pathway would be preferentially activated in MSNs due to the enhanced CAG somatic instability observed in the striatum. To test this hypothesis, we will use molecular, pharmacological and genetic manipulations in primary neurons and transgenic HD mice. The expected results will reveal the mechanism/s by which MSNs become dysfunctional in HD and establish the basis for future understanding of the preferred susceptibility of MSNs to mHTT. Several studies have attempted to pharmacologically activate HSF1 as a therapeutic approach in HD, but they failed in achieving long-term benefits. We propose that preventing HSF1 degradation may be a more effective and long-lasting therapeutic strategy. In Aim 2 we will use pharmacological and genetic manipulations of CK2α’ in HD mice to prevent HSF1 degradation at different time points during disease progression. These studies will reveal the timeframe in which preventing HSF1 degradation is necessary to improve HD symptoms and consolidate CK2α’ as a potential therapeutic target for HD. Changes in HSF1, p53 and CK2 are also observed in other neurodegenerative diseases and therefore, our studies in HD may identify common HSF1 degradative mechanisms and therapeutic targets applicable to other NDs.