Communication breakdown - synaptic dysfunction in Huntington's disease.

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG-triplet expansion in the

gene encoding the protein huntingtin. The disease typically starts in mid-life and progresses for 15-20 years. To date no effective treatment is available for curing the disease. HD primarily affects the striatum, cerebral cortex and hypothalamus. At later stages cell death is evident in the striatum and cerebral cortex. Interestingly, some non-neuronal tissues such as muscle and the endocrine pancreas are also affected. A larger than normal proportion of HD patients develop diabetes mellitus. Traditionally the majority of symptoms were believed to be caused by extensive neuronal

death. However, recent studies indicate that neuronal dysfunction plays a central role for symptom development at the early to middle stages of the disease.

In this thesis we have aimed at (1) studying the proteins involved in neurotransmitter docking and release at the active zones of the presynapse in patient samples and mouse models of HD; (2) assessing the function of the cholinergic neurons in HD and (3) investigating the intracellular transport and release of insulin in insulin-secreting clonal beta-cells expressing wild-type or mutant huntingtin.

We describe a loss of several proteins important for vesicle docking and neurotransmitter release in patient brain samples and in brains from mouse models of HD. Moreover, we have observed a defective synthesis and packaging of acetylcholine in a mouse model of HD and in patient brain tissues. Taken together, these studies indicate that there is a defective neurotransmitter handling and release. Possibly this could underlie some of the cognitive defects and the progressive dementia that are integral parts of HD symptomatology. In beta-cells we detected an early reduction of insulin release in mutant huntingtin expressing cells. The decreased insulin secretion is not explained by decreased insulin synthesis or cell death due to mutant huntingtin. Instead we observed a slowed intracellular transport of insulin-containing vesicles. We suggest that this, in combination with a decreased insulin production, could cause diabetes mellitus in mouse models of HD and in patients.

In summary, we have observed alterations in the intracellular transport, neurotransmitter synthesis, handling and release in cell and mouse models of HD and in HD patient brains. The data indicate that cellular dysfunction, rather than cell death, may underlie some of the early symptoms of HD. This suggests that enhancing synaptic functions may be a novel approach to therapeutic intervention in HD.