Sci. Aging Knowl. Environ., 30 July 2003
Tau might kill neurons by tampering with the cellular skeleton
Key Words: tubulin tauopathy alternative splicing frontotemporal dementia and Parkinsonism associated with chromosome 17
Researchers have tied themselves into knots trying to discover how tangles of the protein tau might kill brain cells in Alzheimer's disease (AD) and other disorders. A new study suggests that an imbalance between two forms of the protein is lethal. An overabundance of one tau version might slay neurons by discombobulating the network of tubes that braces the cell and helps move materials around within it.
Along with amyloid plaques, tau tangles are the hallmarks of AD; they also characterize several rare neurodegenerative illnesses, including one known as FTDP-17. Most researchers think that the snarls poison cells and that mutant forms of tau cause disease because they get stuck in the clumps. However, studies of FTDP-17 have suggested a different death mechanism. Tau comes in two flavors: One contains three segments of a repeating amino acid, and the other contains four such segments. Instead of carrying a faulty tau gene, some FTDP-17 patients make more of the four-repeat version than of the other form, and this disparity provokes brain deterioration. How an oversupply of one tau variety might kill neurons remains uncertain, but the protein's cellular job provided a clue. Tau controls the stability of microtubules, tiny tubes that give a cell its shape, pull chromosomes apart as it splits, and form tracks on which cellular cargo moves. Microtubules are constantly lengthening and shortening, and cell biologist Stuart Feinstein of the University of California, Santa Barbara, and colleagues wanted to determine how tau alters this behavior.
The team allowed microtubules to form in solution and measured how fast they grew or shrank after treatment with one of the two versions of tau. The growing tubes lengthened at about the same rate regardless of the treatment--a little over 40% faster than untreated microtubules did. However, the four-repeat version slowed the rate of shortening by 54%, whereas the three-repeat form reduced it by only 19%. The finding indicates that the four-repeat form is better than the other variety at stabilizing the microtubules and that excess four-repeat tau might make them sluggish, says Feinstein. The results suggest a new hypothesis for how tau kills neurons. A cell needs microtubules that are dynamic--able to grow or shrink when necessary--but not too dynamic, says Feinstein. Anything that upsets the balance could be fatal for the cell. Extra four-repeat tau might restrain the microtubules too much, whereas mutations that disable tau might allow the microtubules to become hyperactive. Whether the relative amounts of the two types changes in AD remains uncertain.
Conventional wisdom blames toxic tangles for the brain degeneration of tau diseases, but this paper presents a compelling alternative, says cell biologist Michelle King of the University of Virginia in Charlottesville. Cellular neuroscientist Lester Binder of Northwestern University's Feinberg School of Medicine in Chicago praises the team for its provocative hypothesis: "This paper doesn't solve the controversy [over how tau kills cells], but it brings it front and center." The researchers are investigating how mutant forms of tau influence microtubules, how the two tau varieties alter stability, and whether they have the same effect in living cells. The answers might tell us whether scientists have finally unraveled the mystery of tau.
--Mitch Leslie; suggested by Amir Sadighi Akha
July 30, 2003
Science of Aging Knowledge Environment. ISSN 1539-6150