Investigator: William Holmes, Rhode Island College
Mentor: Gerald Jogl, Brown University
Scientific Theme: Molecular Toxicology
Abstract: Neurodegenerative diseases cause the gradual loss of neuronal function and eventual cellular death, leading to diseases such as Alzheimer’s, Parkinson’s, and Huntington’s. Over 6 million Americans are currently afflicted with neurodegenerative diseases and as the population ages, cases of neurodegenerative diseases are expected grow exponentially. There is currently no effective cure for any neurodegenerative disease, merely therapies that can mitigate the symptoms of the declining nervous system. While each specific neurodegenerative disease has its specific pathologies, they are all related by the common trait of aggregating protein that leads to cellular toxicity. These proteins tend to form amyloid oligomers or fibers, and these toxic aggregates are linked to cellular death. Different proteins cause the same class of disease suggests a common mechanism of toxicity, yet in vitro studies fail to reveal the source of this toxicity. Understanding the biochemical properties of protein aggregation and its link to cellular toxicity is paramount to develop effective treatments for all neurodegenerative diseases.
The goal of this work is to apply our knowledge of the biochemical properties of these proteins from inside of the cell and study aggregation and toxicity directly. The most common post-translational modification in cells is adding an acetyl group at the amino (N) terminus of the protein. This post-translational modification is not applied to proteins expressed and purified in E. coli, and proteins that lack a modified N-terminus form less stable amyloids, have a greater propensity to aggregate, and can lead to the loss of protein function. Aim 1 of this study will utilize a novel E. coli strain that N-terminally acetylates proteins for purification, where they will be assessed for changes in amyloid formation and cellular toxicity. Aim 2 will study the effects of Nterminal acetylation on chaperone proteins and their ability to prevent amyloid formation and maintain protein homeostasis in the cell. This research will provide Rhode Island College students with experience in a broad range of techniques not currently available.
Human Health Relevance: The goal of this proposal is to understand the fundamental properties of the toxic protein aggregates that can lead to neurodegenerative diseases like Alzheimer’s and Huntington’s. The results from these studies can lead to new drug mechanisms for preventing neuronal loss and potentially to novel diagnostic techniques. Rhode Island College students will have the opportunity to learn a broad range of techniques and contribute to our knowledge of the mechanisms behind these devastating diseases.