Energy metabolism as a target for new treatment strategies in Huntington’s disease

Huntington´s disease (HD) is a fatal inherited neurodegenerative disorder caused by a CAG triplet repeat expansion in the huntingtin (HTT) gene and characterized by cognitive and motoric dysfunctions as well as psychiatric problems. Accumulating evidence, however, suggests altered energy metabolism and a hyper-catabolic state as key features of HD pathology. In clinical HD, body weight has been shown to be a predictor of HD progression and higher BMI is demonstrated to be associated with a slower rate of functional, cognitive and motor decline. Body weight loss, muscle atrophy, body composition and endocrine alterations have been reported in HD patients and animal models of HD prior to weight loss. Different HD mouse models have been used to study disease progression with the R6/2 mouse as the most commonly used mimicking many features of HD clinical symptoms, such as weight loss and muscle atrophy, as well as cognitive and motoric dysfunctions.In paper I, we studied the effect of a higher BMI on HD disease progression in the R6/2 mouse model. By crossing the R6/2 mouse model with the obese leptin-deficient mouse model (Ob/Ob) we generated a novel obese R6/2 mouse model with leptin-deficiency. We showed that it was possible to dramatically increase body weight in R6/2 mice by decreasing energy metabolism. Although, a sign of improvement of repetitive and anxiety-like behavior was seen, this was not associated with improved neuropathological measures.In paper II, we evaluated the effect of ghrelin administration on metabolic disturbances seen in HD. We found that ghrelin reversed the catabolic gene expression profile with increased expression of Caspase 8, Traf-5 and Creb1 seen in R6/2 skeletal muscle, and improved skeletal muscle morphology. Interestingly, behavior deficits were also rescued.In paper III, the effect of liraglutide administration alone or together with ghrelin on brain and peripheral metabolic disturbances was evaluated. We found that liraglutide alone or together with ghrelin normalized glucose homeostatic features in the R6/2 mice. Liraglutide alone decreased brain cortical active GLP-1 and IGF-1 levels, alongside higher ADP levels, while co-administration of liraglutide and ghrelin decreased brain insulin, lactate, AMP and cholesterol levels in R6/2 mice.In study IV, we studied the mechanism underlying a possible satellite cell dysfunction of HD mouse models, using in vivo and in vitro studies. We utilized the R6/2 mouse model to study proliferation and differentiation of satellite cells. Here we found that R6/2 mice exhibit reduced myofiber diameter both in vivo and in vitro, and altered gene expression (Irs2, Myh2, MyoG, Sirt2) and protein levels (MyoD1) in vitro. We found that ghrelin administration increased myofiber diameter and normalized MyoD1 protein levels in differentiated satellite cells derived from R6/2 mice.Taken together, findings provided in this thesis encourage further studies targeting metabolism, giving rise to potential therapeutically interventions in HD