Role of DNA methyltransferases in Huntington's disease

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ABSTRACT Huntington’s disease (HD) is a devastating and invariably fatal neurodegenerative disease characterized by progressive atrophy and loss of specific neurons in the striatum and cortex, leading to motor, cognitive, and psychiatric disorders. The underlying disease mechanism remains poorly understood, and currently, no cure exists for this disease. There is an urgent need to understand the molecular mechanisms driving the death of HD neurons, so that these mechanisms can be harnessed to save these dying neurons. Transcriptional dysregulation is an early molecular abnormality in the course of HD and is thought to contribute to neurodegeneration and disease progression. Although emerging evidence indicates altered patterns of several different epigenetic modifications in HD, key epigenetic modifications that have a causal role in transcriptional changes and neurodegeneration remain largely unknown. DNA methylation, a major epigenetic modification, has recently been shown to be perturbed in mutant Htt-expressing cells and brains of HD patients. Importantly, our recent findings suggest that DNA methyltransferases (DNMTs), enzymes that catalyze DNA methylation, are of functional importance in mutant HD protein (huntingtin)-induced neurotoxicity. The fundamental objective of this proposal is to identify the molecular regulation and role of DNMTs in neuronal dysfunction and death, using mouse and human cultured neurons as well as mouse models of HD. Our hypothesis is that abnormal DNA methylation is a dominant epigenetic event in HD, which drives the dysregulation of genes important for neuronal function and survival, thereby contributing to neuronal dysfunction and death in HD. Targeting this epigenetic pathway may therefore prevent disease progression. To test this hypothesis, we will pursue the following specific aims: 1) Determine how mutant Htt induces aberrant DNA methylation with a focus on DNMT function; 2) Determine the role of DNMTs in HD pathogenesis in mice in vivo; and 3) Identify the mechanism of DNMT inhibition-mediated neuroprotection in mutant Htt-expressing neurons in vitro and in vivo. We will take innovative approaches to isolate cell-type specific RNA and DNA from mouse brain to determine HD-specific DNA methylation and transcription changes in disease-vulnerable neurons in vivo. Our contribution here is expected to establish the critical role of DNMTs in HD pathogenesis using a disease-relevant neuronal system and genetic mouse models in vivo, with the long-term goal of discovering potential therapeutic targets to prevent neurodegeneration in HD. Given the observation of altered transcription and DNA methylation in other neurodegenerative diseases, psychiatric disorders, aging, and learning and memory, the proposed studies have implications for a wide-range of human nervous system conditions as well as normal brain function. Together, our examination of a novel epigenetic mechanism underlying mutant Htt-induced transcriptional dysregulation and neurodegeneration will provide answers to fundamental questions in the field of neurodegenerative diseases.