Article (Scientific journals)
Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly.
Gladwyn-Ng, Ivan; Cordon-Barris, Lluis; Alfano, Christian et al.
2018In Nature Neuroscience, 21 (1), p. 63-71
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Abstract :
[en] 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.
Disciplines :
Neurology
Author, co-author :
Gladwyn-Ng, Ivan ;  Université de Liège - ULiège > Giga - Neurosciences
Cordon-Barris, Lluis
Alfano, Christian ;  Université de Liège - ULiège > Giga - Neurosciences
Creppe, Catherine
Couderc, Therese
Morelli, Giovanni 
Thelen, Nicolas  ;  Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie cellulaire
America, Michelle
Bessieres, Bettina
Encha-Razavi, Ferechte
Bonniere, Maryse
Suzuki, Ikuo K.
Flamand, Marie
Vanderhaeghen, Pierre
Thiry, Marc  ;  Université de Liège - ULiège > Département des sciences de la vie > GIGA-R : Biologie cellulaire
Lecuit, Marc
Nguyen, Laurent  ;  Université de Liège - ULiège > GIGA - Neurosciences
More authors (7 more) Less
Language :
English
Title :
Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly.
Publication date :
2018
Journal title :
Nature Neuroscience
ISSN :
1097-6256
eISSN :
1546-1726
Publisher :
Nature Publishing Group, United Kingdom
Volume :
21
Issue :
1
Pages :
63-71
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 04 January 2018

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