Chromatin mishandling in Huntington disease: potential links to pathogenesis and points of therapeutic intervention

Huntington disease (HD) is a hereditary neurodegenerative disorder that affects 3,000 Canadians. Patients with a HD mutation experience adult-onset psychiatric symptoms, cognitive impairment and motor disturbances that progressively worsen over many years and lead to death. Despite a massive world-wide research effort, there is still no means of prevention, no treatment, and no cure for HD. Recent studies confirm that psychiatric and cognitive changes occur in at-risk individuals several years before formal HD diagnosis. The ability to understand and reverse these early cognitive changes may lead to a cure for HD. Chromatin is the genomic DNA-protein complex that specifies how to make proteins and when and where to do so. Recent studies show that the way genetic material is packaged into chromatin in brain cells can be altered by early life experiences (such as learning), and can affect behaviour. Alterations in chromatin regulation have been observed in depression, bipolar disorder and schizophrenia. Many effective psychiatric drugs have been found to influence chromatin regulation. Mendel Grant is examining a possible link between chromatin and the onset and progression of HD. She is testing her hypothesis that environmentally-responsive chromatin changes (such as those induced by learning) do not function normally in a mouse model of HD. This could underlie cognitive dysfunction observed in HD patients and animal models. If chromatin is shown to be misregulated in HD, the use of FDA-approved neuropsychiatric drugs that alter chromatin regulation could be a promising therapy. Information yielded from this study may also be applicable to other neurodegenerative disorders including Alzheimer and Parkinson diseases and psychiatric conditions such as depression.