Beyond the basal ganglia

Abstract: Huntington’s disease (HD) is a fatal, hereditary disorder caused by a mutation in the gene encoding the protein huntingtin. Although mutant huntingtin is ubiquitously expressed throughout the body, HD research has mainly focused on the role of the basal ganglia. Dysfunction of these brain nuclei likely underlies motor disturbances in HD, including the conspicuous, uncontrollable, dance-like movements (chorea). However, HD is frequently complicated by other important signs and symptoms that cannot, or not solely, be attributed to basal ganglia dysfunction. Among these is unintended weight loss, which occurs in nearly all HD patients and can affect both quality of life and disease progression. Other symptoms that might occur irrespective of basal ganglia dysfunction are cognitive deterioration, psychiatric problems, sleep disturbances, cardiac failure and atrophy of skeletal muscle. The past decade has seen an increasing interest in the role of mutant huntingtin in other areas of the brain and body. Although these effects are still poorly understood, their study could lead to a better understanding of the pathological mechanisms underlying HD, as well as to the identification of novel markers of disease progression and therapeutic options. The aim of this thesis was, therefore, to investigate the effects of mutant huntingtin outside the basal ganglia, especially those structures that might underlie weight loss in HD, including the hypothalamus, adipose tissue, and the gastro-intestinal tract. We found that weight loss in both HD patients and R6/2 mice (a transgenic model of HD) is not caused by changes in caloric intake or locomotor activity. Metabolism was, however, increased in R6/2 mice and this may be the cause of weight loss. Interestingly, weight loss increases with higher CAG repeat number in the mutant gene in both HD patients and R6/2 mice. This suggests that mutant huntingtin affects metabolic rate in a CAG repeat length dependant manner. The mechanism underlying this is unclear, but several regulators of metabolism, including the hypothalamus, were affected in R6/2 mice. In addition, the gastro-intestinal tract is affected in both HD patients and R6/2 mice and malabsorption of nutrients was observed in end-stage R6/2 mice. Although gastro-intestinal dysfunction is unlikely to be the cause of weight loss in HD, it may play an important role in the acceleration of weight loss in the final stages of the disease. The findings in this thesis demonstrate that mutant huntingtin does not only affect the areas that have traditionally received the most attention in HD research, i.e. the basal ganglia. Other areas in the brain and body, such as the hypothalamus and gastro-intestinal tract, are also affected. Dysfunction of these structures could account for weight loss as well as several other, yet poorly understood, signs and symptoms of HD. Elucidation of the role of mutant huntingtin throughout the body could provide a better understanding of HD pathogenesis, lead to the development of novel markers of disease progression, and open new avenues for treatment.