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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/26578

Title: Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly
Authors: Gladwyn-Ng, Ivan
Cordon-Barris, Lluis
Alfano, Christian
Creppe, Catherine
Couderc, Therese
Morelli, Giovanni
Thelen, Nicolas
America, Michelle
Bessieres, Bettina
Encha-Razavi, Ferechte
Bonniere, Maryse
Suzuki, Ikuo K.
Flamand, Marie
Vanderhaeghen, Pierre
Thiry, Marc
Lecuit, Marc
Nguyen, Laurent
Issue Date: 2018
Citation: NATURE NEUROSCIENCE, 21(1), p. 63-73
Abstract: Accumulating evidence support a causal link between Zika virus (ZIKV) infection during gestation and congenital microcephaly. However, the mechanism of ZIKV-associated microcephaly remains unclear. We combined analyses of ZIKV-infected human fetuses, cultured human neural stem cells and mouse embryos to understand how ZIKV induces microcephaly. We show that ZIKV triggers endoplasmic reticulum stress and unfolded protein response in the cerebral cortex of infected postmortem human fetuses as well as in cultured human neural stem cells. After intracerebral and intraplacental inoculation of ZIKV in mouse embryos, we show that it triggers endoplasmic reticulum stress in embryonic brains in vivo. This perturbs a physiological unfolded protein response within cortical progenitors that controls neurogenesis. Thus, ZIKV-infected progenitors generate fewer projection neurons that eventually settle in the cerebral cortex, whereupon sustained endoplasmic reticulum stress leads to apoptosis. Furthermore, we demonstrate that administration of pharmacological inhibitors of unfolded protein response counteracts these pathophysiological mechanisms and prevents microcephaly in ZIKV-infected mouse embryos. Such defects are specific to ZIKV, as they are not observed upon intraplacental injection of other related flaviviruses in mice.
Notes: Nguyen, L (reprint author), Univ Liege, GIGA Neurosci, Interdisciplinary Cluster Appl Genoprote GIGA R, CHU Sart Tilman, Liege, Belgium. marc.lecuit@pasteur.fr; lnguyen@ulg.ac.be
URI: http://hdl.handle.net/1942/26578
DOI: 10.1038/s41593-017-0038-4
ISI #: 000423155800014
ISSN: 1097-6256
Category: A1
Type: Journal Contribution
Appears in Collections: Research publications

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