Abstract
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded polyglutamine repeat in the huntingtin protein. Neuropathology in the basal ganglia and in the cerebral cortex has been linked to the motor and cognitive symptoms whereas recent work has suggested that the hypothalamus might be involved in the metabolic dysfunction. Several mouse models of HD that display metabolic dysfunction have hypothalamic pathology, and expression of mutant huntingtin in the hypothalamus has been causally linked to the development of metabolic dysfunction in mice. Although the pathogenic mechanisms by which mutant huntingtin exerts its toxic functions in the HD brain are not fully known, several studies have implicated a role for the lysososomal degradation pathway of autophagy. Interestingly, changes in autophagy in the hypothalamus have been associated with the development of metabolic dysfunction in wild-type mice. We hypothesized that expression of mutant huntingtin might lead to changes in the autophagy pathway in the hypothalamus in mice with metabolic dysfunction. We therefore investigated whether there were changes in basal levels of autophagy in a mouse model expressing a fragment of 853 amino acids of mutant huntingtin selectively in the hypothalamus using a recombinant adeno-associate viral vector approach as well as in the transgenic BACHD mice. We performed qRT-PCR and Western blot to investigate the mRNA and protein expression levels of selected autophagy markers. Our results show that basal levels of autophagy are maintained in the hypothalamus despite the presence of metabolic dysfunction in both mouse models. Furthermore, although there were no major changes in autophagy in the striatum and cortex of BACHD mice, we detected modest, but significant differences in levels of some markers in mice at 12 months of age. Taken together, our results indicate that overexpression of mutant huntingtin in mice do not significantly perturb basal levels of autophagy.
Highlights
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by the amplification of a polyglutamine stretch at the Nterminus of the huntingtin protein [1]
The successful expression of either wt or mutant htt forms in rAAV5-htt853-18Q and rAAV5htt853-79Q mice was verified by qRT-Polymerase Chain Reaction (PCR) as well as Western blot (Figure 1B, C)
Metabolic dysfunction with obesity and insulin as well as leptin resistance can be observed in genetic models of HD expressing human full-length htt, such as the YAC and BACHD mice [24,26,83]
Summary
Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by the amplification of a polyglutamine stretch at the Nterminus of the huntingtin (htt) protein [1]. It has been widely recognized that HD patients experience severe cognitive and psychiatric disturbances, which occur years before the onset of the motor impairment [5,6,7]. These symptoms significantly affect the life of the patients and their relatives [8]. Cortico-striatal changes are likely to be important for the cognitive changes but less is known about the other non-motor aspects of the disease.
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