In neurons, the protein tau normally helps to form and support microtubules—necessary for creating the long highways in axons that traffic proteins and other cell components from place to place. But in several diseases, including Alzheimer’s and other forms of dementia, tau abandons its supporting role and instead begins to aggregate in the body of the cell. Exactly how tau inflicts damage in the brain is still unknown. But a study by Mel Feany’s lab, published online Dec. 24 in Nature Cell Biology, introduces a new connection: tau not only binds to microtubules but also directly interacts with another structural protein, actin. In a fruit fly model of tau-induced neurodegeneration, the team found that tau causes filaments of actin to bundle and accumulate in neurons, which may be a novel mechanism of neurodegeneration.
The Eyes Have It
Feany, HMS associate professor of pathology at Brigham and Women’s Hospital, has been studying the pathology of tau in fruit flies, which can quickly be screened for genes that might influence disease. Fruit flies engineered to express normal human tau—or one of the mutant versions implicated in familial neurodegeneration—experience toxicity in the brain and eyes. As part of their studies, the researchers screened for genes involved in tau-mediated pathology; one of the proteins that surfaced encoded a protein that binds to actin. Studies had shown that actin may interact with tau in vitro, but whether the interaction was relevant in the living brain was unclear.
Postdoctoral fellow Tudor Fulga investigated the role of actin in the fly model by manipulating actin in the eyes of flies. The tau-expressing flies develop an eye with a ragged-looking surface and damage at the retina, which can serve as a marker for toxicity. When Fulga increased actin levels in the flies, he saw a dramatic change: the eyes were almost completely destroyed. Actin can either exist as lone molecules or it can collect into filaments. When Fulga expressed a protein that destabilizes actin filaments, the damage to the eye was significantly lessened. The team found a similar effect when tinkering with actin in the brains of adult flies that express tau. “If you destabilize actin, you can rescue the adult brain degeneration, while if you overexpress actin, loading the cell with too much, the degeneration is much more severe,” Fulga said.
From these studies, the team hypothesized that actin’s ability to form filaments played a critical role in the havoc caused by tau. Using in vitro and in vivo methods, Fulga found that tau binds directly to actin filaments and causes these filaments to line up together to form bundles. Tau is more likely to have this effect when phosphate groups are attached to it—a change that is thought to be central to its role in human disease.
The two hallmarks of Alzheimer’s disease are amyloid plaques and tau-rich tangles. But Feany points out that another type of lesion is also found in the brains of people with the disease: Hirano bodies, rod-shaped structures rich in actin. “People have known about Hirano bodies for a long time,” she said, but little research has been devoted to them, and their potential role in the pathology of Alzheimer’s is completely unknown. The team examined the brains of flies expressing tau and found that they contained structures similar to Hirano bodies. Most of the rod-shaped structures contained actin, and many also contained tau. Feany’s group teamed up with the lab of Brad Hyman, the John B. Penney Jr. professor of neurology at HMS and Massachusetts General Hospital, to look at the brains of transgenic mice expressing a mutant form of tau. The same actin-rich rods were present in the brains of those mice.
Feany’s team then wanted to see whether actin might serve as a link between tau and the other key protein in Alzheimer’s disease, amyloid beta (Abeta). Ilan Elson-Schwab, a graduate student in the lab, created a line of flies that expresses human Abeta and tau. These flies developed much more severe toxicity with more actin aggregations in the brain than those expressing tau alone, suggesting that Abeta enhances tau’s effects on actin.
The flies that Elson-Schwab created will also be useful for studying potential links between Abeta and tau. Feany explained that research on amyloid plaques and tau tangles has been parallel but largely separate, in part because it is difficult to reproduce both pathologies together in animals. The proteins are found in different locations—tau in the cell and Abeta outside of it—but some chain of events appears to connect them both to neurodegeneration.
Feany’s team also plans to use their model to better understand actin’s role in neurodegeneration. Bruce Yankner, HMS professor of pathology, said the study shows an intriguing connection between the two critical but separate structures in cells, microtubules and the actin cytoskeleton. “It suggests that crosstalk between the two components is dysregulated by these changes in tau,” he said. “This opens up a new area of investigation.” Actin has not been seen as an important player in neurodegeneration, though there is some evidence that an accumulation of actin can cause cells to undergo apoptosis. The evidence in fruit flies must prove itself in higher organisms, Yankner added, but “if it pans out, it will certainly provide new therapeutic targets.”
Feany said that drugs already exist that interfere with actin filaments, and these can now be tested in flies for their effects on neurons.
