Therapeutics for Microcephaly - The Three “M”s

Abstract

Event Abstract Back to Event Therapeutics for Microcephaly - The Three “M”s Ivan GLADWYN-NG1*, Ivan Gladwyn-Ng1*, Christian Alfano1, Giovanni Morelli2, Michelle America3, Celine D'Alessandro1 and Laurent Nguyen1 1 GIGA-Neurosciences, University of Liège, Belgium 2 Biomedical Research Institute, Hasselt University, Belgium 3 Department of Biology, KU Leuven, Belgium Neurodegenerative and neurodevelopmental disorders are increasingly prevalent diseases (1; 2; 3) with significant socio-economic costs (4; 5; 6). We present a conceptual work plan for investigating neurodevelopmental causes of microcephaly towards identifying potential drug candidates based on our recent publication (7) and EU patent application (8). Emerging epidemiological and clinical articles report the causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. Presently, we highlight results from combinatorial analyses of ZIKV-infected human foetuses and mouse embryos to elucidate underlying cellular and molecular mechanisms pf ZIKV-induced MIC. Firstly, we demonstrate that ZIKV triggers endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) in the cerebral cortex of infected post-mortem human foetuses. Secondly, we designed an in vivo mouse model - via intracerebral (ICV) and intraplacental (IPL) infection - that recapitulates the clinical phenotype. In combination, the ER stress in human foetuses and embryonic mouse brains perturbs a physiological UPR within cortical progenitors that controls neurogenesis. Thirdly, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained ER stress subsequently leads to apoptosis. Lastly, we demonstrate that administration of pharmacological inhibitors of the UPR counteracts these pathophysiological mechanisms and abrogates ZIKV-induced MIC in murine embryos and pups. In conclusion, we demonstrate a conceptual work plan to elucidate pathophysiological mechanisms underlying genetic and acquired causes of MIC, as well as to investigate putative compounds that potentially ameliorate these neurodevelopmental disorders. Figure 1 Figure 2 Figure 3 Acknowledgements CORDON-BARRIS, Lluis; CREEPE, Catherine; COUDERC, Thérèse; THELEN, Nicolas; BESSIÈRES, Bettina; ENCHA-RAZAVI, Férechté; BONNIÈRE Maryse; SUZUKI, Ikuo K.; FLAMAND, Marie; VANDERHAEGHEN, Pierre; THIRY, Marc; LECUIT, Marc.