How does a specific class of proteins regulate the structure of tau and its effects on nerve cells in neurodegenerative disease?

2016 Mechanisms of Cellular Death in Neurodegeneration Grant

Researching

Causes

Tau protein plays an important role in Alzheimer’s and other neurodegenerative diseases. The normal function of tau is to act as molecular scaffolding inside cells and to help transport nutrients. The physical structure of this protein is critical for its proper function. However, in Alzheimer’s disease tau is often modified, leading to abnormal forms of tau building up in nerve cells to form tau tangles – a hallmark of Alzheimer’s disease. This build-up of tau is thought to be directly related to nerve cell damage.

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,” can regulate tau modification and structure. This class of proteins may be a promising target for preventing or reducing brain cell damage associated with the abnormal build-up of tau protein.

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 treatments. These studies may advance our understanding of how proteins accumulate in the brains of people with Alzheimer’s disease and other dementias, which we hope could ultimately lead to new strategies for disease prevention.

Dr John Koren 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 a harmful build-up of tau protein and is more toxic to nerve cells. Others are beneficial, and modify tau in a way that reduces its toxic effects. The research team is working to further characterise 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 mice showing the hallmark features of Alzheimer’s disease. The researchers hope to determine which PPIases speed up nerve cell damage in these mice, and which PPIases help tau protein maintain its proper structure and function with the hope of harnessing the process to a beneficial outcome.

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Awarded to
Dr John Koren III

Institution
University of South Florida

Full project name
The role of peptidyl-prolyl isomerases in tau-mediated neurotoxicity

This project is funded through a global funding collaboration, called Mechanisms of Cellular Death in Neurodegeneration (MCDN), between Alzheimer’s Research UK, Alzheimer’s Association and the Weston Brain Institute.