Lieberman Team -Identifying the cellular machinery that degrades polyQ AR
Summary Description
The machinery that enables cells to get rid of misfolded proteins within the nucleus is not well understood. Additionally, we don’t know if this machinery is made up of the same components in different cell types. These are critical unknowns in Kennedy’s disease, as the misfolded polyglutamine androgen receptor (polyQ AR) protein accumulates within the nucleus of motor nerve cells and skeletal muscle cells to cause the disease. We hypothesize that identifying the components of this machinery will provide key insights into how the disease happens and identify possible targets for future therapies.
To test this idea, we will use a fruit fly model of Kennedy’s disease that reproduces important aspects of the disease in humans, including decreased mobility and shortened lifespan. We will efficiently look for components of the machinery that gets rid of the misfolded polyQ AR. We will do this by crossing Kennedy’s disease flies to a library of mutant flies that lack various components of machines that are known to degrade misfolded proteins. Our objective is to see which of these components is helping flies get rid of the polyQ AR in the nucleus of their motor nerve cells and skeletal muscle cells.
Our long-term goal is to identify the important components of this machinery in human cells. We have a human embryonic stem cell line with the Kennedy’s disease mutation, and we can differentiate these cells into motor nerve cells and skeletal muscle. We will use these cells to identify the components of the machinery that gets rid of the misfolded polyQ AR in human cells. We will do this by selectively decreasing the expression of various components of machines known to get rid of misfolded proteins, and then testing to see which ones are important for getting rid of the polyQ AR protein. We will start by testing some components that are suggested by published studies in the literature and then move on to test hits that are identified from our studies in fruit flies. We expect to identify that machinery that works in the nucleus of human motor nerve cells and skeletal muscle to get rid of the polyQ AR.
