The Impact and Mechanistic Basis of Chaperone AMPylation in the Development and Progression of Alzheimer’s Disease

Proteins are small particles that enable us to think and store memories. As we get older, these proteins become less and less stable and will occasionally engage in the formation of protein clumps within cells. Some of these protein clumps are very toxic to neurons and will damage our brains, thus triggering neurodegenerative diseases such as Alzheimer’s disease. We aim to better understand the processes that prevent the formation of such protein clumps and seek to learn why these processes become less efficient in the older population.

Our work examines the impact and mechanistic basis of chaperone regulation in the development and progression of Alzheimer’s disease. Chaperones are small molecular machines required for the repair and disposal of damaged proteins. Dysregulation of chaperone activity facilitates the formation of protein clumps characteristic for Alzheimer’s disease. Recently, it was discovered that chaperones are regulated by a chemical modification called AMPylation. The goal of our research project is to define how chaperone AMPylation levels correlate with Alzheimer’s disease onset and development. We will examine human brain samples from Alzheimer’s disease patients as well as controls using high-content microscopic imaging and biochemical approaches to elucidate how chaperone AMPylation might contribute to this disease. Our approach combines exciting novel techniques and experiments that allow us to define the chaperone AMPylation status in both fixed or frozen human brain tissue. The results from our work will dramatically increase our understanding of how chaperone AMPylation regulates protein aggregation and represent the first in-depth analysis of protein AMPylation levels in human brains. Since the regulation of chaperone activity is critical in all aggregation-associated neurodegenerative diseases, including Parkinson’s disease, Huntington’s diseases or inherited spinocerebellar ataxias, our work will have implications beyond Alzheimer’s disease. Our ultimate long-term goal is to explore and exploit the pharmacological modulation of chaperone AMPylation as a novel avenue to combat Alzheimer’s disease.