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Therapeutic approaches to dementia and depression in Huntington’s disease

Huntington’s disease (HD) is an inherited single-gene abnormality that causes neurons in the brain to become dysfunctional and eventually die.

Aims

Our first approach to therapy is to examine the effects of environmental enrichment (enhanced cognitive stimulation and physical activity).  We have previously demonstrated that environmental enrichment can delay onset of the depression and dementia in HD.  We will now examine the effect of the increased mental activity and physical exercise at the level of specific molecules in the brain.  Those molecules which are beneficially modulated by this intervention will be identified as candidate targets for ‘enviromimetics’, drugs which mimic or enhance the beneficial effects of environmental stimulation.

The condition involves cognitive deficits (culminating in dementia), psychiatric symptoms (the most common of which is depression), and a movement disorder (including the uncontrollable ‘dance-like’ symptoms called chorea). HD is one of the increasing numbers of fatal brain diseases known to be caused by DNA expansion (a ‘genetic stutter’) in the disease-causing gene.  In the case of HD, the gene mutation is translated into a toxic protein which slowly poisons subpopulations of cells in the brain.

Our previous research into Huntington’s disease (HD) has shown that we can use a mouse model of HD to understand the debilitating symptoms of depression and dementia. We have also identified key molecules involved in the depression and dementia that occurs in HD. The aim of this project is to identify key molecules associated with depression and dementia in HD, and to test a therapeutic intervention in a mouse model of HD.  We are using transgenic mice which express the gene mutation that causes HD in humans.  We are focusing on key molecules that we think may be involved in the disease process, including those located at synapses, the connections between neurons.   We use molecular biology and biochemistry approaches to measure changes in the candidate molecules in key brain regions, including the cerebral cortex and basal ganglia.  

There are no effective disease-modifying treatments for this devastating disorder, so any new candidate therapeutic intervention we can identify has the potential to directly help HD families.  Furthermore, the disease processes in HD are highly relevant to other brain disorders including Parkinson’s disease, Alzheimer’s disease, other forms of dementia, and depression. Therefore this project will also have an impact outside of HD.

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