Harvard researchers have expressed the wildtype and mutant forms of human tau protein in Drosophila, creating a new model for one aspect of Alzheimer’s disease pathology as well as for tauopathies. In tomorrow’s Science, Mel Feany and collaborators report that young fruit flies hatch with normal nervous systems but as adults develop progressive neurodegeneration and accumulate abnormal tau protein in their brains. Lifespan was reduced by about 25 percent in those that harbor the normal tau gene and by about 60 percent in those that express the mutant version found in the human disease FTDP-17.
Surprisingly, however, the fly brains did not appear to contain neurofibrillary tangles, which abound in the brains of patients with FTDP-17 or other tauopathies such as progressive supranuclear palsy or cortical basal degeneration. The researchers could not find aggregates in an EM analysis of 519 neurons in different mutant strains, but they caution that they cannot exclude the presence of occasional tangles or small filaments.
These results are consistent with the notion that tangles may not be required for the disease process in humans, Feany says. Rather, tangles might be a neuron’s attempt to store away misfolded or hyperphosphorylated tau protein that is toxic and cannot be properly degraded.“Our data leave open the possibility that [tangles] are in fact protective,” says Feany. “This would suggest that therapies aimed at dissolving tangles may not be successful and may be deleterious.”
Feany is currently using second site modification and other fast methods of fly genetics to work out the molecular mechanism by which tau becomes toxic. Testing such a mechanism in higher organisms will also enable her to address the question of how relevant the fruit fly truly is to human disease. (Fly neurons are small, lack neurofilaments, and degenerate within days to weeks.)
The fly model did mirror two important features of human neurodegeneration, says Feany. For one, normal tau was toxic, just as tau-related toxicity even without a mutation in the tau gene is seen in Alzheimer's and certain tauopathies. Mutant tau, however, was more toxic, again as seen in humans. For another, tau toxicity was somewhat specific to cholinergic neurons, which are especially vulnerable to degeneration in AD.—Gabrielle Strobel
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- Wittmann CW, Wszolek MF, Shulman JM, Salvaterra PM, Lewis J, Hutton M, Feany MB. Tauopathy in Drosophila: neurodegeneration without neurofibrillary tangles. Science. 2001 Jul 27;293(5530):711-4. PubMed.