The microtubule-associated protein tau is the major component of the intracellular neurofibrillary tangles (NFT) found in patients with various neurodegenerative disorders, including Alzheimer's and frontotemporal dementia. Scientists know that hyperphosphorylation of tau is at the root of its pathology, but what impact other proteins have on tau-related cell damage is less certain. In today's Neuron, George Jackson and colleagues at UCLA show that components of the wingless signal transduction pathway contribute to tau toxicity in flies.
Jackson et al. used a fruit fly model of tauopathy pioneered by Mel Feaney at Harvard Medical School (see ARF news item). In Jackson's hands, overexpression of human wild-type tau in the flies led to gross malformations of the compound eye. This effect was exacerbated by overexpression of glycogen synthase kinase-3 (GSK-3, the fly homolog is called shaggy), which is known to attenuate wingless signaling in Drosophila and has previously been fingered as a tau kinase and potential drug target in Alzheimer's (Anderton et al., 2000; Eldar-Finkelman, 2002; see ARF news item).
Interestingly, overexpression of another stepping stone in the wingless pathway, the fly homolog of human β-catenin, (armadillo), also exacerbated the effect of tau. This suggests that GSK-3's role in tauopathy lies outside of the wingless pathway, as one of its normal functions is to turn off armadillo in response to wingless signaling. Furthermore, the authors found that the transcription factor TCF, which is turned on by the wingless pathway, also exacerbated tau's damage to the eye.
Taken together, the data suggests that GSK-3 has dual, conflicting roles. On the one hand, it attenuates wingless signaling, and should, therefore, ameliorate the effects of armadillo and TCF on tau. But on the other hand shaggy itself exacerbates the effects of tau. The authors found that tau was hyperphosphorylated when co-expressed with GSK-3, making it tempting to conclude that the two directly interact.—Tom Fagan
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- Jackson GR, Wiedau-Pazos M, Sang TK, Wagle N, Brown CA, Massachi S, Geschwind DH. Human wild-type tau interacts with wingless pathway components and produces neurofibrillary pathology in Drosophila. Neuron. 2002 May 16;34(4):509-19. PubMed.