Illuminating the Functions of Genes Mutated in Alzheimer’s Disease

I will elucidate how disrupted lysosomal activity in microglia contributes to the pathology in Alzheimer’s disease (AD) using large-scale CRISPR mutagenesis screens of genes associated with AD risk.As a postdoctoral researcher, I have identified a lysosomal transcriptional network necessary for the survival and function of microglia. I am currently building upon my observation to functionally define a lysosomal network in microglia that is disrupted in Alzheimer’s disease (AD). Despite the wealth of genomic data available from AD patients, the functions of most genes associated with AD risk loci remain uncharacterized. As an independent researcher, I will elucidate the functions of AD risk-associated genes in microglia, with a special focus on genes functioning in lysosomal pathways.

My research is primarily focused on immune cells of the brain referred to as microglia. Microglia chew up dead cells and fight infections in the brain to make sure that other brain cells, such as neurons, function normally. To do their jobs, microglia require a special structure called the lysosome. The lysosome is frequently thought of as the garbage disposal or the recycle bin of the cell. When microglia eat bacteria or dead material, this material passes through the lysosome, where it gets recycled or broken up into smaller pieces. In Alzheimer’s disease patients, microglia are important for clearing up amyloid-beta plaque deposits; these are most easily thought of as debris that must be cleaned out for the normal function of brain cells. Initially, microglia are successful in eating up the debris deposits, passing them through the lysosome to make smaller chunks, and thus eliminating the deposits. However, in time, microglia start making mistakes and start chewing up healthy neurons and other important cells nearby. We have a lot of data to show that changes in DNA sequence – called mutations – in Alzheimer’s disease patients occur in genes that are important for microglia or lysosomes. I will study how these genes are important for the normal activity of microglia and lysosomes and how, over time, they can cause microglia to switch from being good for the brain to harming brain cells.

Despite strong evidence indicating that microglial dysfunction is a core feature of Alzheimer’s disease (AD), it remains unclear how genes associated with AD risk loci affect microglial function, and how disrupted microglial function, in turn, can impact the onset or progression of AD. The large-scale, screen-based approach I propose is necessary to provide the first insight into the functions of most genes associated with AD risk loci and will bridge the gap between the rich genomic resources available for AD and the molecular mechanisms underlying this devastating disease.

My study will lead to a deeper understanding of lysosomal gene networks necessary for microglial function, which can be harnessed to develop effective therapeutic strategies for Alzheimer’s disease (AD) by modulating lysosomal activity. Furthermore, I anticipate that my proposed large-scale functional genomics screen of genes associated with AD risk loci will: a) illuminate novel functions for genes mutated in AD, and b) reveal novel genes associated with the pathology of AD. Collectively, my proposed research will have a tremendous positive impact on AD, microglia, and zebrafish communities.