TAU-ANNONACIN · Effects of systemic annonacin exposure in transgenic mice expressing normal or mutant human tau protein: role of environment-gene interactions in neurodegeneration

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

Experimental and epidemiological studies have identified natural substances, such as the acetogenin annonacin, which could be associated with mechanisms of neurodegeneration in some forms of tauopathies (Champy et al., 2004). Many mutations in the tau gene have also been associated with familial cases of tauopathies, such as the frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17) (Lee et al., 2001). However, the relative contribution of genetic and environmental factors to the observed neurodegenerative changes and the way in which specific genetic backgrounds affect the susceptibility towards the exposure to environmental toxins are still unclear. 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 led 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 inhibited complex I, on the tau protein. We found that annonacin exposure caused an increase in the number of neurons with phosphorylated tau in the somatodendritic compartment in several brain areas, with such an effect being only observed in mice that expressed a mutated human tau (R406W mutation) as opposed to mice that either overexpressed the wild-type human tau (hWT +/-) or had only the endogenous mouse tau (hWT -/-). We also found evidence suggestive that the annonacin effect was at least partly mediated through a proteasome dysfunction. 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.

Data: CORDIS, © European Union