Forschungs- & Entwicklungsinformationsdienst der Gemeinschaft - CORDIS


TAU-ANNONACIN Berichtzusammenfassung

Project ID: 980039
Gefördert unter: FP6-MOBILITY
Land: Brazil

Final Activity and Management Report Summary - TAU-ANNONACIN (Effects of systemic annonacin exposure in transgenic mice expressing normal or mutant human tau protein: environment-gene interactions)

Experimental and epidemiological studies have associated natural toxins, such as the acetogenin annonacin, with mechanisms of neurodegeneration in some forms of tauopathies (Champy et al., 2004). On the other hand, many mutations in the tau gene have been associated with familial cases of tauopathies, such as the frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17) (Lee et al., 2001). Although, it is widely accepted that both genetic and environmental factors are likely to contribute to the observed neurodegenerative lesions, it is remains unclear how specific genetic backgrounds affect the susceptibility towards the exposure to environmental toxins.

The goal of this proposal was to investigate gene-environment interactions using experimental models of Tau-associated neurodegeneration. We proposed to determine whether there was a pathogenetic synergy between annonacin intoxication and mutations in the tau gene that lead to FTDP-17.

We used transgenic mice bearing specific genetic backgrounds (Lee et al., 2005) to study the effects of annonacin, a natural mitochondrial toxin that inhibits complex I, on the tau protein.

In the first phase of the project, we found that annonacin exposure causes an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas, and such effect was observed only in mice that expressed a mutated human tau (R406W mutation; Zhang et al., 2004) as opposed to mice that had only the endogenous mouse tau (hWT -/-).

In the second phase of the project, we sought to find the possible molecular mechanisms involved and found evidence suggestive that annonacin effect is partly mediated through a proteasome dysfunction associated with tau kinase activation. In summary, we found a synergistic interaction between annonacin exposure and the presence of an FTDP-17 mutation that resulted in increased phosphorylation of neuronal tau.


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