Grant: Fellowship - Priority Announcement: Huntington's Disease

The aim of this proposal is to investigate the molecular mechanisms underlying Huntington Disease (HD). HD is an inherited, progressive disorder that is characterised by abnormalities of mood, movement, thinking and personality. Although the disease affects only approximately 5 in 100,000 people worldwide, innovative research must be performed in this area as there are no cures or effective treatments. HD has been linked to a single gene mutation that leads to production of the mutant huntingtin protein (mhtt). HD is associated with severe dysfunction and degeneration of the striatum, a brain area important for motor coordination and cognitive function. Glutamate is the most abundant excitatory neurotransmitter in the brain, and it activates the N-methyl-D-aspartate (NMDA)-type glutamate receptor (NMDAR), important for mediating neuronal communication and facilitating learning and memory. However, over-activation of this receptor can lead to cell death - referred to as "excitotoxicity" - that is thought to be enhanced in HD. Mouse models have been developed to understand better the mechanisms underlying this neurological disorder. The study will therefore use an HD mouse model to investigate the effects of mhtt on the molecular mechanisms underlying neuronal, cognitive and behavioural abnormalities. Using biochemical and imaging techniques, I will investigate why there is increased NMDAR activation and how this is linked to signalling cascades that trigger neuronal cell death. Manipulating the activity of NMDAR associated cellular proteins may prevent the activation of detrimental signalling pathways. It is important to determine the molecular mechanisms that lead to altered NMDAR activity in order to facilitate the discovery of new drug targets that may lead to more effective and specific treatments for this devastating disease.