CHARACTERIZING THE FUNCTION OF HUNTINGTIN IN THE CELL STRESS RESPONSE AS A TARGET FOR DRUG DISCOVERY IN HUNTINGTON’S DISEASE

Abstract

<p>Huntington’s disease (HD) is a devastating autosomal dominant neurodegenerative disorder for which there are no disease modifying treatments. Owing to this are the multiple biological functions of the huntingtin protein and the lack of understanding of the exact pathways being affected in HD. It is clear that the huntingtin protein normally provides anti-apoptotic support and that there are underlying energetic problems and cell stress defects associated with disease. Work from our group has shown that huntingtin acts as a stress sensor and translocates from the endoplasmic reticulum to the nucleus upon cell stress. We therefore hypothesized that huntingtin has a nuclear function in the cell stress response; which would tie together what is currently known about huntingtin, its pro-apoptotic function and the energetic defects of neurodegeneration. In this thesis we describe huntingtin as having a role in the nuclear cofilin-actin rod stress response. Cofilin is an actin binding protein normally involved in actin treadmilling. During stress, cofilin saturates F-actin leading to rod formation which functions to alleviate ATP. We show that this response is impaired in the presence of mutant huntingtin and that the aberrations in this response can be mediated through the enzyme tissue transglutaminase. Little is known about the physiological role and requirement of the cofilin-actin rod response. Therefore we created a system to test if rod formation was required in cells during stress, which indicates if and how targeting this pathway will be possible. We additionally looked at targeting the nuclear import and export properties of the cofilin protein, which directly affect rod formation and may be targetable in cofilin modifying drug discovery efforts. Overall, this work has described a specific and relevant pathway affected by mutant huntingtin and started the process of assessing this pathway as a therapeutic avenue for Huntington’s disease.</p>