The pathogenesis of Huntington's Disease (HD) is as yet unknown but there is substantial evidence that both altered gene transcription as well as mitochondrial dysfunction play an important role. There is evidence that huntingtin binds to transcription factors which results in decreased expression of genes which may play a critical role in neuronal survival. A secondary consequence of this appears to be impaired oxidative phosphorylation and increased generation of reactive oxygen species. In our prior grant, we showed that there was impaired oxidative phosphorylation in transgenic mouse models of Huntington's disease, and that this was associated with increased oxidative damage. We also showed that agents such as creatine and coenzyme Q, which improve cellular bioenergetics, exert neuroprotective effects in transgenic mouse models of Huntington's disease. In the present proposal, we intend to extend these studies to two further unique transgenic mouse models of Huntington's disease. We will determine whether there is mitochondrial dysfunction and oxidative damage in a knock-in mouse model developed by MacDonald and colleagues. These mice are a very accurate genetic model of Huntington's disease. We will also examine the tetracycline-off model developed by Yamamoto and colleagues to determine whether there is mitochondrial dysfunction and oxidative damage with the gene turned on, which then resolves once the gone is turned off. We will carry out similar studies with an inducible cell culture model. We will investigate whether histone deacetylase (HDAC) inhibitors exert neuroprotective effects by altering gene transcription in transgenic mouse models of Huntington's disease. We will examine whether a phosphodiesterase IV inhibitor can exert neuroprotective effects in transgenic mouse models of HD by increasing cyclic AMP levels, leading to increased CREB transcriptional activity, and whether this improves mitochondrial function. Our prior studies showed that combinations of agents, which target different disease mechanisms in Huntington's disease, may exert additive neuroprotective effects. We will, therefore, examine whether a combination of creatine or coenzyme Q with either a HDAC inhibitor or a phosphodiesterase IV inhibitor can exert additive neuroprotective effects. ? ?
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