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2016 Grants - Dickey
The Role of Peptidyl-prolyl Isomerases in Tau-mediated Neurotoxicity
Chad A. Dickey, Ph.D.
University of South Florida
Tampa, Florida, United States
2016 Mechanisms of Cellular Death in Neurodegeneration (MCDN)
How does a specific class of proteins regulate the structure of tau and its effects on nerve cells in neurodegenerative disease?
Tau protein plays an important role in Alzheimer’s and other neurodegenerative diseases. Tau protein’s normal function is to stabilize the internal scaffolding of cells and help transport nutrients. The physical structure of tau protein is critical for its proper function. However, in individuals with Alzheimer’s disease, tau protein is often modified, leading to abnormal forms of tau that accumulate in nerve cells, a hallmark of Alzheimer’s disease. This build-up of tau is thought to be directly related to nerve cell destruction, or neurotoxicity.
Some modifications to tau protein structure are more harmful than others and each modification is performed by a specific protein in the brain. One newly identified class of proteins, called “peptidyl-prolyl cis/trans isomerases,” or “PPIases,” are enzymes that can regulate tau modification and structure. This class of proteins may be a promising target for preventing or reducing brain cell damage associated with abnormal tau protein accumulation.
Chad A. Dickey, Ph.D. and colleagues have identified several PPIases that affect tau protein structure in different ways. Some of these PPIases modify tau in a way that leads to harmful accumulation of tau protein and increased nerve cell death. Others are beneficial, and modify tau in a way that reduces its toxic effects. The research team will further characterize the interactions of tau protein and PPIases using nerve cells grown in a laboratory dish. They will also determine the effects of PPIases added to the brains of Alzheimer’s-like mice. The researchers hope to determine which PPIases accelerate neurotoxicity in these mice, and which PPIases help tau protein maintain its proper structure and functionality with the hope to harness the process to a beneficial outcome.
The results of these studies will shed new light on the molecular mechanisms that underlie nerve cell death in neurodegenerative diseases; we have little understanding of this process and much to gain from effectively controlling it. The PPIases represent an understudied class of proteins that may serve as targets for the development of future therapeutics. These studies may advance our understanding of how proteins accumulate in the brains of individuals with Alzheimer’s disease, which may ultimately lead to new strategies for disease prevention.