Sci. Aging Knowl. Environ., 10 March 2004
Sticking It to Tau
Enzyme tags tau with deadly decorations
Hanging out with the wrong crowd is bad for teenagers and for proteins. New research shows that consorting with a particular enzyme can convert the brain protein tau into a cell killer. The work bolsters the hypothesis that phosphate additions to tau underlie its lethal transformation.
Along with -amyloid plaques, tangles of the protein tau are one of the hallmarks of Alzheimer's disease (AD) (see "Detangling Alzheimer's Disease"). Knots of tau also characterize several rare neurodegenerative diseases (see Frontotemporal Dementia Case Study), and neuroscientists have confirmed that the protein can slay cells. Tangles abound with tau molecules that are studded with phosphate groups, suggesting that these additions make the protein poisonous. However, researchers haven't been able to confirm that hypothesis. Fly geneticist Bingwei Lu of Stanford University and colleagues wanted to test whether extra phosphates twist tau into a killer and to figure out how the process begins.
The researchers focused on an enzyme called PAR-1 kinase that attaches phosphate groups to tau. To gauge tau's toxicity, they measured its ability to kill cells in the eyes of fruit flies. They inserted a genetic switch into the cells that allowed them to control production of PAR-1. Cranking up the enzyme withered the flies' eyes, indicating that phosphorylated tau was slaying neurons. Boosting a weakened version of PAR-1 caused less damage, and an inert version of the enzyme had no effect. Those results strengthen the case that sticking phosphates on tau makes it lethal. Further work showed that neurons lacking PAR-1 were less than a third as likely to kill themselves than were those that make the protein.
Other enzymes glue phosphate to several places on tau, but PAR-1 affixes the molecules at only two sites. When the researchers engineered flies to make a version of tau in which the amino acids at these sites rebuff phosphate, the insects sported normal eyes--even in the presence of extra PAR-1. Moreover, the altered tau molecules accumulated fewer phosphate groups at other attachment points. Changing one of these amino acids instead of those at the PAR-1 sites didn't make tau less poisonous. Together, the results suggest that PAR-1's actions are crucial for making tau toxic, says Lu, and that its meddling allows other phosphates to glom on.
The study "makes the case that phosphorylation of tau can be a cause of toxicity," says neuroscientist Lester (Skip) Binder of Northwestern University's Feinberg School of Medicine in Chicago, Illinois. However, he notes that in AD, the attachment sites in tau don't accumulate phosphates in the same order as in the fly protein. The difference suggests that the human version of PAR-1 might not be the instigator of phosphate addition in AD. Now, researchers need to determine how phosphates corrupt tau, says biochemist John Lew of the University of California, Santa Barbara. The chemical modifications might cause tau to become noxious, or they could disrupt its normal job of stabilizing the tiny tubes that haul organelles and other cellular contents around (see "The Halting Way of Tau"). Further work might reveal how to shield tau from a bad influence.
March 10, 2004
Science of Aging Knowledge Environment. ISSN 1539-6150