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
Image
Figure 2
Image
Figure 3
Image

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.

References

1. Erkkinen MG, Kim MO, Geschwind MD. Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. Cold Spring Harb Perspect Biol. 2018 Apr 2;10(4). pii: a033118. doi: 10.1101/cshperspect.a033118. Review. PMID: 28716886 2. Younger DS. Epidemiology of Childhood and Adult Mental Illness. Neurol Clin. 2016 Nov;34(4):1023-1033. doi: 10.1016/j.ncl.2016.06.010. Epub 2016 Aug 18. Review. PMID: 27719986 3. EU Joint Programme – Neurodegenerative Disease Research. http://www.neurodegenerationresearch.eu accessed 2018 August 01. 4. Raggi A, Leonardi M. Burden and cost of neurological diseases: a European North-South comparison. Acta Neurol Scand. 2015 Jul;132(1):16-22. doi: 10.1111/ane.12339. Epub 2014 Oct 23. PMID: 25345990 5. Olesen J, Gustavsson A, Svensson M, Wittchen HU, Jönsson B; CDBE2010 study group; European Brain Council. The economic cost of brain disorders in Europe. Eur J Neurol. 2012 Jan;19(1):155-62. doi: 10.1111/j.1468-1331.2011.03590.x. PMID: 22175760 6. Gustavsson A, Svensson M, Jacobi F, Allgulander C, Alonso J, Beghi E, Dodel R, Ekman M, Faravelli C, Fratiglioni L, Gannon B, Jones DH, Jennum P, Jordanova A, Jönsson L, Karampampa K, Knapp M, Kobelt G, Kurth T, Lieb R, Linde M, Ljungcrantz C, Maercker A, Melin B, Moscarelli M, Musayev A, Norwood F, Preisig M, Pugliatti M, Rehm J, Salvador-Carulla L, Schlehofer B, Simon R, Steinhausen HC, Stovner LJ, Vallat JM, Van den Bergh P, van Os J, Vos P, Xu W, Wittchen HU, Jönsson B, Olesen J; CDBE2010Study Group. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol. 2011 Oct;21(10):718-79. doi: 10.1016/j.euroneuro.2011.08.008. Epub 2011 Sep 15. PMID: 21924589 7. Gladwyn-Ng I, Cordón-Barris L, Alfano C, Creppe C, Couderc T, Morelli G, Thelen N, America M, Bessières B, Encha-Razavi F, Bonnière M, Suzuki IK, Flamand M, Vanderhaeghen P, Thiry M, Lecuit M, Nguyen L. Stress-induced unfolded protein response contributes to Zika virus-associated microcephaly. Nat Neurosci. 2018 Jan;21(1):63-71. doi: 10.1038/s41593-017-0038-4. Epub 2017 Dec 11. PMID: 29230053 8. Nguyen L, Alfano C, Gladwyn-Ng I, Cordon-Barris L, Creepe C. Patent application: UPR inhibitors against neurodevelopmental disorders. Application number #EP17153834.1, 2017 January 31, Co-inventor, The European Union

Keywords: neurodevelopment, Human fetus brain, mouse brain, Neurogenesis, patent, unfolded protein response (UPR), endoplasmic recticulum, Drug candidate, animal model, Zika associated adverse outcomes of pregnancy

Conference: Belgian Brain Congress 2018 — Belgian Brain Council, LIEGE, Belgium, 19 Oct - 19 Oct, 2018.

Presentation Type: e-posters

Topic: NOVEL STRATEGIES FOR NEUROLOGICAL AND MENTAL DISORDERS: SCIENTIFIC BASIS AND VALUE FOR PATIENT-CENTERED CARE

Citation: GLADWYN-NG I, Gladwyn-Ng I, Alfano C, Morelli G, America M, D'Alessandro C and Nguyen L (2019). Therapeutics for Microcephaly - The Three “M”s. Front. Neurosci. Conference Abstract: Belgian Brain Congress 2018 — Belgian Brain Council. doi: 10.3389/conf.fnins.2018.95.00003

Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters.

The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated.

Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed.

For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions.

Received: 02 Aug 2018; Published Online: 17 Jan 2019.

* Correspondence:
Dr. Ivan GLADWYN-NG, GIGA-Neurosciences, University of Liège, Liege, Belgium, ivangladwynng@gmail.com
Dr. Ivan Gladwyn-Ng, GIGA-Neurosciences, University of Liège, Liege, Belgium, i.gladwynng@uliege.be