Environment Gene Interaction in Essential Tremors Specific Aims of the Proposal:

Objective: The P301S mutation in exon 10 of the tau gene causes a hereditary tauopathy. While mitochondrial complex I inhibition has been linked to sporadic tauopathies. Piericidin A is a prototypical member of the group of the piericidins, a class of biologically active natural complex I inhibitors, isolated from streptomyces spp. with global distribution in marine and agricultural habitats. The aim of this study was to determine whether there is a pathogenic interaction of the environmental toxin piericidin A and the P301S mutation. Methods: Transgenic mice expressing human tau with the P301S-mutation (P301S) and wild-type mice at 12 weeks of age were treated subcutaneously with vehicle (N510 P301S, N57 wild-type) or piericidin A (N59 P301S, N59 wild-type mice) at a dose of 0.5 mg/kg/d for a period of 28 days via osmotic minipumps. Tau pathology was measured by stereological counts of cells immunoreative with antibodies against phosphorylated tau (AD2, AT8, AT180, and AT100) and corresponding Western blot analysis. Results: Piericidin A significantly increased the number of phospho-tau immunoreactive cells in the cerebral cortex in P301S mice, but only to a variable and mild extent in wild-type mice. Furthermore, piericidin A led to increased levels of pathologically phosphorylated tau only in P301S mice. While we observed no apparent cell loss in the frontal cortex, the synaptic density was reduced by piericidin A treatment in P301S mice. OPEN ACCESS Citation: Höllerhage M, Deck R, De Andrade A, Respondek G, Xu H, et al. (2014) Piericidin A Aggravates Tau Pathology in P301S Transgenic Mice. PLoS ONE 9(12): e113557. doi:10.1371/ journal.pone. 0113557 Editor: Emmanuel Planel, Centre Hospitalier de l’Université Laval, Canada Received: May 14, 2014 Accepted: October 29, 2014 Published: December 1, 2014 Copyright: 2014 Höellerhage et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper. Funding: This work was supported by the Deutsche Forschungsgemeinschaft (HO2402/6-1, HO2402/8-1), the German Ministry of Education and Research (BMBF GEF 10-54), Science and Technology Development Fund (Egypt, GEF 1054), and the German Academic Exchange Service (DAAD to ACdA, HX, MS). Wolfgang H. Oertel is Senior research Professor of the Charitable Hertie Foundation, Frankfurt/Main, Germany. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. PLOS ONE | DOI:10.1371/journal.pone. 0113557 December 1, 2014 1 / 16 Discussion: This study shows that exposure to piericidin A aggravates the course of genetically determined tau pathology, providing experimental support for the concept of gene-environment interaction in the etiology of tauopathies.