INVESTIGATOR: William Holmes, Rhode Island College
COLLABORATIVE MENTOR: Nicolas Fawzi, Brown University
THEME: Neuroscience

ABSTRACT: Neurodegenerative diseases result in the progressive loss of cognitive or motor function due to the death of nervous tissue. It is estimated that 6.5 million Americans are currently afflicted with a neurodegenerative disease, and this number is expected to double in the next 20 years. Current treatment of neurodegenerative diseases aims to treat the symptoms, but there is no effective strategy to halt the death of neuronal tissue. What is causing neuronal cells to die? One common characteristic of neurogenerative diseases is that neurons accumulate protein aggregates, and these aggregates appear to be toxic to the cell. But the question remains, what causes these proteins to aggregate and why are they toxic to the cell? By studying the process of protein aggregation, we can begin to investigate the link between aggregation and toxicity. Understanding this connection is vital to develop treatments that prevent neuronal cell death, and not simple treat the symptoms of neurodegenerative disease. The goal of this proposal is to further understand the process of protein aggregation by studying a specific protein called Tau. Multiple neurodegenerative diseases, such as Alzheimer’s, Traumatic Brain Injury (TBI – concussions) Frontotemporal dementia, are linked to Tau aggregation. Much of our current knowledge is based off of studying the carboxy (C) terminus of Tau, however the structure and function of the amino (N) terminus remains unclear. Additionally, the N terminus of Tau is modified with an acetyl group, which alters the stability a protein related to Parkinson’s Disease. Taken together, the goal of this proposal is to understand how the modification and structure of the N terminus of Tau participate in aggregation. Specifically, aim 1 will study the structural changes to the N- terminus upon loss of an acetyl group. Aim 2 will identify changes to the formation and stability of Tau aggregates. This research will also enable Rhode Island College students to collaborate and utilize equipment at a research- intensive environment at Brown University.

RELEVANCE: The goal of this proposal is to understand the complex structural dynamics of the protein Tau. The results from this proposal will inform us potential methods to disrupt Tau aggregation before it becomes toxic to neurons. Additionally, this proposal will directly engage Rhode Island College undergraduate students in biomedical research and give them exposure to modern techniques in cellular and structural biology.