Experimental and epidemiological studies have identified natural substances, such as the acetogenin annonacin, that could be associated with mechanisms of neurodegeneration in some forms of tauopathies. Many mutations in the taugene have also been associated with familial cases of tauopathies, such as the frontotemporal dementias with parkinsonism linked to chromosome 17 (FTDP-17). However, it is still not clear what is the relative contribution of genetic and environmental factors to the observed neurodegenerative changes (neuronal loss and pathological tau aggregation) and how specific genetic backgrounds affect the susceptibility towards the exposure to environmental toxins. The goal of this proposal is to investigate gene-environment interactions using experimental models of Tau-associated neurodegeneration.We propose to determine whether there is a pathogenetic synergy between annonacin intoxication and mutations in the tau gene that lead to FTDP-17. Our proposal will take advantage of the transgenic mouse technology to study the effects of a natural toxin on animal models bearing specific genetic background. The results obtained may also increase our understanding of physiopathogenic mechanisms of major neurodegenerative diseases where a gene-environm ent interaction appears to play a role as is the case of Parkinson's and Alzheimer's diseases. The proposed research project has emerged from a consortium of three groups in Europe (Germany, France, Guadeloupe) in cooperation with an experienced researcher from a developing country (Brazil). The realization of the proposed work will strongly strengthen the infrastructure of cooperation between the European partners and will contribute to the human capacity building in the area of neurodegeneration in Brazil.