In humans, neurofibrillary tangles in patients with Alzheimer disease (AD) and several other neurodegenerative disorders contain a hyperphosphorylated form of the microtubule-associated protein tau. Mutations in TAU have also been linked to a rare inherited form of frontotemporal dementia. Now it appears that flies coaxed to hyperphosphorylate tau may also have symptoms of neurodegeneration.
In the 16 May Neuron, Jackson et al. present results from flies engineered to overexpress tau. Tau overexpression set the stage for asking whether known modifiers of tau could lead to tangles. The researchers focused on glycogen synthase kinase-3 (GSK-3), called shaggy in flies. This member of the Wnt signaling pathway phosphorylates tau in vitro and in mice, and interacts with other proteins implicated in AD, such as presenilin. The researchers found that overexpressing shaggy and human tau resulted in the hyperphosphorylation of tau, neurofibrillary tangles and cell death, all hallmarks of neurodegeneration.
On the right is a fly eye overexpressing shaggy and human tau, and on the left is an eye overexpressing only human tau. The eyes are stained for DNA (green) and with antibodies that recognize phosphorylated tau (red). In subsequent experiments using antibodies to cell components sensitive to cell death, the researchers found that the shaggy-overexpressing cells underwent apoptosis − that's consistent with the nuclear disorganization seen with DNA stains (right). Only in the presence of excess shaggy does tau form neurofibrillary tangles (on right and in inset) and initiate cell death.
The new data help clear up the question of whether hyperphosphorylation of tau is a cause, rather than a consequence, of tangle formation. In fact the researchers saw evidence of cell death before the formation of tangles, hinting that it may be tau itself and not tangle formation per se that leads to neurodegeneration. The fly model is particularly useful for genetic screens to look for additional modifiers of tau − and this study leads the way. The authors point out that in human disease, it may be defects in modifiers of tau, rather than tau itself, that initiate the neurodegenerative process.
(GSK-3
