Tau Tangler: Protein promotes dementia-associated conglomerations in flies (Neurodegenerative disease)
Authors: Davenport R. John 
Published: August 2003

Sometimes, even a well-behaved child can get into a tangle if prodded by a friend. A new study pinpoints a molecule that urges an otherwise docile protein to snarl up fly neurons. The engineered flies used in the experiments are the first to recreate an abnormal protein aggregate associated with human dementia.

When a protein called tau clumps inside neurons, neurofibrillary tangles result. These protein thickets sprout in people afflicted with diseases such as Alzheimer's (see
"Detangling Alzheimer's Disease"
and
Honig Case Study
). Scientists are hunting for other molecules that encourage the aggregation: Some mutations in the
tau
gene make the protein gummier than usual, but many people with dementia have the normal form of
tau
. Tangled tau carries more phosphate molecules than the free-floating version, and an enzyme called glycogen synthase kinase-3β (GSK-3β) tacks those chemical groups onto tau. But no one knew if GSK-3β encouraged tangle formation.

To probe the relation between tau and GSK-3β in living creatures, Jackson and colleagues engineered fruit flies to express gobs of the normal, human version of tau. The researchers then mated the insects with other flies that carried extra GSK-3β. Their offspring suffered more severe neurodegeneration--gauged by the loss of neurons going to the eye--than did the flies that only produced tau. And a fluorescently labeled antibody that recognizes tangles illuminated eye tissue from the hybrid flies but not from either of the parent strains. Apparently, tau needs GSK-3β to form neurofibrillary tangles. "They've done something that nobody yet has done," says geneticist Simon Lovestone of Kings College, London. "They've shown that GSK-3β enhances tangle formation."

The researchers next investigated whether GSK-3β enlisted the help of other molecules to instigate tangling. GSK-3β is part of the so-called
wingless
signaling pathway, which helps assign cellular roles during embryonic development. Jackson and colleagues wondered if other components of the pathway besides GSK-3β also affect neurodegeneration. They bred tau-producing flies with those carrying a mutated form of the gene that encodes β-catenin, a protein deactivated by GSK-3β. They reasoned that if GSK-3β triggers tangling by turning off β-catenin, the offspring should suffer more severe neurodegeneration than would flies with normal β-catenin and extra tau. Instead, the flies were healthier. And flies with supplemental β-catenin and tau bore more neural defects than flies with tau alone. The results support the notion that GSK-3β directly modifies tau, rather than prodding other components of the
wingless
pathway to do the job.

The work exposes a key contributor to tangle formation, but GSK-3β's role isn't certain. Other researchers have found that GSK-3β alleviates tau's havoc, although the discrepancy is reconcilable. It appears to stem from differences in the amount of GSK-3β that the cell makes, according to geneticist Fred van Leuven of Catholic University in Leuven, Belgium. Future work will need to address whether neurons lose function before tangle formation, adds Lovestone. With GSK-3β's role in tangling tau coming into focus, drug designers will likely take it more seriously as a target for dementia therapies. Such drugs, like good parents, could steer tau away from trouble.

--R. John Davenport

G. R. Jackson, M. Wiedau-Pazos, T.-K. Sang, N. Wagle, C. A. Brown, S. Massachi, D. H. Geschwind, Human wild-type tau interacts with
wingless
pathway components and produces neurofibrillary pathology in
Drosophila. Neuron
34
, 509-519 (2002).
[Abstract]
[Full Text]