A peripheral immune response in Huntington's disease and delineation of its importance in disease pathology

Abstract: Huntington’s disease (HD) is a fatal, hereditary disease for which there is no cure. It is caused by a mutation in a gene called huntingtin. HD is a so-called neurodegenerative disease, where there is a loss of neurons in areas of the brain that control body movements. This results in uncontrolled dance-like movements (chorea). Traditionally, research on HD has focused round the brain and what is causing the neurodegeneration. There are however other symptoms that cannot be overlooked. Patients are suffering from weight loss despite adequate intake of nutrition. They also suffer from muscle wasting, cognitive deterioration, psychiatric problems, sleep disturbances, cardiac failure and a subtle increase in inflammatory proteins. These symptoms further affect the quality of life and disease progression for patients with HD. The overall aim of this thesis was to investigate the mechanism behind elevated levels of inflammatory proteins previously detected in HD patients, and how that could affect other aspects of disease pathology, such as muscle wasting. We isolated cells of the immune response, from both HD patients and three different mouse models of HD, and studied their activity as well as function. These studies led us to further investigate intracellular signaling pathways involved in immune cell-function. We also wanted to investigate gene expression in skeletal muscle from a mouse model of HD and to investigate if and how inflammatory proteins could affect muscle cells in culture. Our studies of immune cell-activation showed that immune cells from both HD patients and from three different mouse models of HD produce higher levels of inflammatory proteins when activation is triggered. This seems to be caused by the direct interaction of the mutant huntingtin protein with a signaling pathway called NFκB. We could also see that there are changes in the expression of genes involved in muscle contraction and the immune response in skeletal muscle, and by stimulating muscle cells in culture with inflammatory proteins known to be elevated in HD, we could furthermore see a change in these genes. The results of this thesis warrants for further investigations into the inflammatory response in HD and how it may affect the disease. The findings also support future studies of anti-inflammatory treatment in HD.