Proteasome-interacting proteins in tau degradation
MentorBradley Hyman, MD, PhD Massachusetts General Hospital
Characteristic accumulations of the “Tau” protein is one of the most important hallmarks of Alzheimer's disease, and tau turnover is a major focus in the study of Alzheimer’s disease causes and treatment. This study seeks to understand the molecular mechanism of tau degradation by the “ubiquitin-proteasome” system, which is the most important proteolytic system in neurons, necessary for the destruction of damaged or unneeded proteins. The focus of this study is on proteasome-interacting proteins that may help deliver misfolded tau to the proteasome for digestion.
The most important hallmarks of Alzheimer's disease are protein aggregates called plaques and tangles in the brain. Plaques form from amyloid beta aggregates outside the cell, and tangles are comprised of tau protein aggregates inside neurons. We do not yet understand why aberrant forms of amyloid beta and tau accumulate in Alzheimer’s disease brains. This study seeks to understand the cellular machinery that digests tau proteins inside neurons. The focus is on the most important protein-digesting enzyme in the cell, called the proteasome. We will examine how proteasomes and their interacting partners digest tau proteins in neurons. This will help us understand why tau fails to be digested when Alzheimer’s disease occurs and how to prevent tau build-up in Alzheimer’s disease. We will directly examine the proteasome in postmortem brain tissues of normal and Alzheimer’s disease subjects and compare their differences. The goal is to identify proteasome-interacting factors that promote tau digestion. Next, we will use cultured nerve cells and animal models of Alzheimer’s disease to study how these factors influence tau digestion and reduce tau pathology. Our innovative approach, combining new ways to isolate proteasomes and to identify associated factors by mass spectrometry, will allow us to characterize, for the first time, proteasomes from Alzheimer’s disease brains. This is likely to provide insights into how the brain tries to cope with aggregates and what can be done to improve our natural coping strategies.