Presenter: Brooke Larson
Authors: Brooke Larson
Faculty Advisor: Brooke Hollien
Institution: University of Utah
A hallmark of neurodegenerative diseases like Alzheimer’s, Parkinson’s and Huntington’s disease is the accumulation of misfolded proteins in neuronal cells. These improperly folded proteins become toxic to the cells and can cause neuronal cell death if not properly disposed of. Misfolded proteins can also arise in the Endoplasmic Reticulum (ER), an organelle responsible for folding and trafficking proteins. When a protein is misfolded in the ER it’s targeted for degradation at the proteasome, an organelle responsible for clearing unwanted proteins in the cell. This prevents misfolded proteins from regularly accumulating in the cell. However, when the ER can’t perform its function, the cell enters a state of ER stress and toxic misfolded protein accumulate in the cell like in neurodegenerative diseases. During ER stress misfolded proteins are degraded through a different pathway leading to the lysosome, an organelle that degrades cell components. This path helps cells reestablish protein homeostasis and prevent cell death. It’s currently unclear how or why cells use an alternative degradation pathway during ER stress. We predict the misfolded proteins are being redirected to this alternative degradation pathway before reaching the proteasome to prevent overwhelming it during ER stress allowing it to remain active. Alternatively, misfolded proteins could be targeted to the proteasome, overwhelming it and then targeted for lysosome degradation. My research project determines when this switch occurs by evaluating the activity of the proteasome during ER stress. To test this question, I created a cell line overexpressing a protein known to be degraded by the proteasome. This proteins also tagged so its levels and hence its proteasome degradation can be measured using western blot technology. This investigation into the detailed mechanisms of how cells clear misfolded proteins, could reveal potential targets for therapeutic drug treatments of neurodegenerative diseases.