Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disorder that causes characteristic motor, psychiatric and cognitive disturbances. Currently, there is no cure or effective treatment for Huntington's disease, which is relentlessly progressive leading to death in 10-25 years. This disease affects approximately 35,000 Americans and another 175,000 are at genetic risk for developing it. Pathologically, Huntington's disease is characterized by the selective vulnerability of particular populations of neurons in the striatum, most prominently, but also in other brain regions. The genetic mutation responsible for Huntington's disease is a triple-repeat expansion in the coding region of a specific protein of unknown function, named huntingtin. It appears that a protein-level alteration of the normal function of huntingtin is responsible for the disease phenotype and it has been postulated that protein-protein interactions are affected leading eventually to neuronal death. Proteolysis of the mutant huntingtin may play a role, whereby an abnormal and ultimately toxic N-terminus fragment of huntingtin is released. This fragment has been shown in humans and animal and cellular models to from aggregates in the nucleus and cytoplasm of neurons. Transglutaminases have been hypothesized to catalyze aggregation and it has been suggested that the huntingtin aggregated may be toxic. The mechanism of this toxicity is unknown, however these aggregates could cause intracellular transport and localization disturbances due to their large size or they could bind and interfere with the function of other protein constituents of the cytoplasm and nucleus. Other studies, primarily using cell culture models, however, have suggested that huntingtin aggregates might be benign or even protective. Thus, it remains unproven that huntingtin aggregation contributes to HD pathogenesis. The first Specific Aim will directly address this question by examining huntingtin aggregate in human Huntington's disease and animal models and correlating their presence with neuropathology that occurs.
In Specific Aim two, we will examine whether transgutaminase inhibition affects aggregation and phenotypic expression in Huntington's disease transgenic mice. Clear pathways from mutant huntingtin or huntingtin aggregates to known mechanisms of cell death have not yet been established. Nevertheless, there is increasing experimental and pathologic evidence that neuronal death in Huntington's disease occurs by an excitotoxic mechanism linked to an underlying energetic defect and oxidative damage leading ultimately to apoptotic cell death. We have shown that oxidative injury is involved in animal models of Huntington's disease using mitochondiral toxins and that it may also be in human Huntington's disease. We have preliminary evidence that coenzyme Q10, an antioxidant, and creatine, an energy buffer, can extend survival in transgenic models of Huntington's disease.
In Specific Aim 3, we will examine oxidative injury as a mechanism of neuronal death by seeking markers of oxidative stress in transgenic models of Huntington's disease and b breeding these animals with transgenic models of Huntington's disease and by breeding these animals with transgenic lines expected to moderate or worsen oxidative injury.
In Specific Aim 4, we will examine apoptosis as a mechanism of cell death in transgenic HD animals by direct examination and by crossing tem with transgenic animal lines relevant to apoptotic death.
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