2023 Alzheimer's Association Research Fellowship (AARF)
Degrading Pathogenic Tau Conformers Through 20S Proteasome Activation
How can a cell structure designed to remove waste from the brain best prevent the accumulation of dementia-related tau protein?
Bryan Ryder, Ph.D.
University of California
San Francisco, CA - United States
Background
The brain cell’s nutrient and energy transport system is organized in parallel strands like railroad tracks. These tracks allow nutrients to travel across the cell, delivering key materials throughout the cell, providing them with energy and keeping them healthy. Tau protein normally helps keep the tracks straight. In Alzheimer’s and other brain diseases, however, the shape of tau becomes modified or “misfolded,” a change that may lead to tau clumps (such as oligomers and tangles) that can damage brain cells and promote memory loss.
One way abnormal tau may accumulate in the brain is when nerve cells lose their ability to clear waste effectively. Research has shown that a part of the cell structure called the “proteasome” acts like a garbage disposal and removes tau and other unwanted proteins. In Alzheimer’s disease, the proteasome may become dysfunctional and fail to remove tau from the brain. This loss of function may be linked to how the proteasome is structured. Studies have found that the proteasome involves several core particles. One particle, called the 20S complex, must interact with another particle called a proteasome activator (PA) in order to carry out its protein-clearing functions. According to research, certain PAs enable the 20S complex to clear tau more effectively than others. But in aging brains, the 20S complex may interact with PAs that do not effectively activate its protein-clearing ability – leading to drastically reduced tau clearance and increased tau clumping in the brain.
Research Plan
Dr. Bryan Ryder and colleagues will study tau clearance by the 20S proteasome using engineered brain cells grown in a laboratory dish. To better understand how the proteasome removes tau, the researchers will determine exactly where interactions take place between the 20S complex and the tau protein molecule. They will also identify molecules and protease activators that optimally trigger tau clearance by the 20S proteasome.
Impact
The results of this study will help clarify the mechanisms underlying tau accumulation in Alzheimer’s disease. They could also identify proteasome activators as novel drug therapies for the disease.