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Totally tubular journey shows how microtubules affect brain health and disease

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On June 13, 2014, the National Institutes of Health (NIH) reported the findings of a molecular-level journey into microtubules. Microtubules are the hollow cylinders inside brain cells that act as skeletons and internal highways. Scientists studied how a protein called tubulin acetyltransferase (TAT) labels the inside of these microtubules. “This is the first time anyone has been able to peer inside microtubules and catch TAT in action,” said Antonina Roll-Mecak, Ph.D., lead investigator of the study. The results of this study provide insight into how TAT tagging works and its importance in brain health. These results were published in the journal Cell.

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TAT coats specific locations inside microtubules with a chemical called an acetyl group. Microtubules are constantly tagged by proteins in the cell to designate them for specialized functions, in the same way that roads are labeled for fast or slow traffic or for maintenance. Defects in the tagging of microtubules are linked to neurodegenerative disorders such as Alzheimer’s disease and may also lead to some forms of cancer. There are an estimated 70,000 people living with Alzheimer's disease in Connecticut (5.2 million in the U.S.). Projected estimates indicate this number will rise to 91,000 (7.1 million in the U.S.) by the year 2025.

“Our study uncovers how TAT may help cells distinguish between stable microtubules and ones that are under construction,” said Dr. Roll-Mecak. High levels of microtubule tagging are unique to nerve cells. This may be the reason that they have complex shapes allowing them to make elaborate connections in the brain. Scientists have known for decades that the insides of long-lived, stable microtubules were often tagged with acetyl groups by TAT. But, the process and exact function of this post-translational tagging remains unclear. Studies have shown that blocking this form of microtubule tagging leads to nerve defects, brain abnormalities, or degeneration of nerve fibers.

Using a variety of techniques (including X-ray crystallography, in vitro acetylation assays, mathematical modeling, and single-molecule TIRF assays), scientists found that TAT surfs through the inside of microtubules and although it can find acetylation sites quickly, the process of adding the tag occurs slowly. They also found that TAT molecules fit poorly into the acetylation sites on tubulin molecules. “It looks as though TAT can easily journey through microtubules spotting acetylation sites but may only label those that are stable for longer periods of time,” said Dr. Roll-Mecak. This may help cells identify the microtubules they need in order to rapidly change shapes. Further studies may explain how microtubule tagging influences nerve cells in health and disease.

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