Mechanisms underlying metabolic alterations in Huntington's disease. Beyond the brain and back

Abstract: Huntington’s disease is caused by a mutation in the gene that codes for the protein huntingtin (HTT). A therapeutic strategy for Huntington’s disease is to lower the levels of huntingtin in the brain. However, multiple clinical trials have been stopped due to adverse effects. This indicates that there is still a lot that we do not understand about huntingtin. Similarly to other neurodegenerative diseases like Parkinson’s disease, Huntington’s disease is caused by cell death in the basal ganglia in the brain. This results in symptoms of the motor systems that facilitate our movements. A hallmark of Huntington’s disease is chorea, which are involuntary movements that worsen over time. However, Huntington’s disease differs from many other neurodegenerative diseases in that huntingtin is expressed throughout the whole body. Therefore, the mutation in huntingtin not only affects the brain but the whole body. What we know is that when our normal huntingtin protein is mutated it becomes harmful to cells and tissues. In some cases, mutant huntingtin causes cell death. In other cases, huntingtin disturbs or changes the function of the cells; the cells loose important functions or gain new functions that can be harmful. In Huntington’s disease there are also memory problems, psychiatric- and metabolic symptoms (“non-motor symptoms”). Several changes occur in the peripheral tissue, for example there is muscle wasting over time (muscle atrophy), heart problems, the production of insulin can deteriorate and there is weight loss that occurs regardless of high caloric intake and/or high appetite. By investigating how body weight and metabolism are affected by the change in huntingtin, new treatment alternatives can be found. A candidate region to study is the hypothalamus in the brain that is central for communication between the brain and periphery. The hypothalamus controls functions such as energy balance and the endocrine system.Mouse models can be used to study Huntington’s disease by reproducing certain features of the disease. We use mice in which a normal copy of the huntingtin gene has been replaced with a mutant copy. In these mouse models, we can see that both tissues in the brain and periphery involved in the control of metabolism are affected by mutant huntingtin, such as the hypothalamus and the adipose tissue. The metabolic symptoms also differ between different mouse models of Huntington’s disease.The thesis consists of three projects, where we have shown that:• By increasing the levels of mutant huntingtin in the hypothalamus, we can cause early body weight gain• Higher levels of huntingtin in the hypothalamus causes changes in gene expression• Certain types of cells in the hypothalamus are more sensitive than others to elevated levels of huntingtin. Brain cells that produce orexin (regulates appetite, sleep, and metabolism) and enzymes that act on histamine and dopamine synthesis are affected early• Before weight loss, there are changes in body fat, for example a redistribution in cell size from larger to smaller fat cells