Grant: Foundation Grant

Neurodegenerative dementias are the fourth leading cause of death worldwide, affecting >24 million people at a cost of >US$172 billion annually. Despite a lot of effort, apart from a handful of mildly effective symptomatic treatments there are no proven ways of stopping these diseases. This proposal addresses takes an innovative approach to develop therapies that address this unmet need. The program is built upon our recent success in identifying genes that carry DNA variants that increase risk of dementia. We have noticed that these genes cluster into functional groups ("cellular pathways"). Two of the largest clusters are of particular interest. One cluster regulates the function of brain inflammatory cells (microglia), which search the brain for damaged cells and aggregated proteins. Another function of these cells is to prune unwanted nerve connections (synapses). The other cluster contains proteins that can change their conformation in order to facilitate key cellular functions (such as making proteins in synapses that are crucial for memory, or regulating the function of microglial cells). Because these clusters contain multiple different genes with DNA sequence changes that increase risk of dementia, it is clear that these clusters govern pathways that are very important in causing synaptic damage leading to dementia. A vital clue is that some of the genes in these pathways also contain variants that actually protect the patient from developing clinical disease. This clearly suggests that mimicking the effect of these protective genetic variants could be a way of preventing/slowing the progression of these diseases. The current program will therefore develop a better understanding of the components in these disease causing pathways, understand how they are regulated, and identify specific components that could be used as molecular targets for treatments that would make the pathway function normally.