Grant: Operating Grant

The demographics of our aging population present alarming future economic and social challenges for our health care systems. Effective therapies are not available to reduce the burdens of neurodegenerative diseases such as Alzheimer's, Parkinson's and Huntington's. Thus, it is urgent to understand the basic mechanisms leading to these severe neurological disorders to block their development at an early onset stage. Protein misfolding and aggregation are associated with these diseases and often originate from inefficient degradation of unwanted proteins. The key enzyme to break down unwanted proteins is called the proteasome. While some cells in our body like skin cells continually grow and divide to replace themselves, most cells like nerve cells in the brain do not divide and are growing old in a non-growing or quiescent state. During quiescence hundreds of metabolic enzymes are sequestered with proteasomes into special droplets in the cytoplasm. These droplets arise from the nucleus of the cell and clear when cells resume growth. The organizing principles behind these droplets remain a mystery. Yeast is established as an excellent model organism to study metabolic pathways as they are easy to grow and manipulate. We will study how these droplets form and their effect on proteasome action. In particular, can we activate proteasomes to degrade unwanted proteins like those found in neurodegenerative diseases? Our studies in yeast will foster new ideas relevant to understanding the biology of the quiescent state in human cells in health and disease.