Zika Virus NS4A and NS4B Proteins Deregulate Akt-mTOR Signaling in Human Fetal Neural Stem Cells to Inhibit Neurogenesis and Induce Autophagy

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

Download Full-text

Integrin αvβ5 Internalizes Zika Virus during Neural Stem Cells Infection and Provides a Promising Target for Antiviral Therapy

Cell Reports ◽

10.1016/j.celrep.2019.11.020 ◽

2020 ◽

Vol 30 (4) ◽

pp. 969-983.e4 ◽

Cited By ~ 9

Author(s):

Shaobo Wang ◽

Qiong Zhang ◽

Shashi Kant Tiwari ◽

Gianluigi Lichinchi ◽

Edwin H. Yau ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Antiviral Therapy ◽

Zika Virus ◽

Promising Target

Download Full-text

Zika Virus Alters DNA Methylation of Neural Genes in an Organoid Model of the Developing Human Brain

mSystems ◽

10.1128/msystems.00219-17 ◽

2018 ◽

Vol 3 (1) ◽

Cited By ~ 26

Author(s):

Sylvie Janssens ◽

Michael Schotsaert ◽

Rahul Karnik ◽

Vinod Balasubramaniam ◽

Marion Dejosez ◽

...

Keyword(s):

Dna Methylation ◽

Stem Cells ◽

Neural Stem Cells ◽

Human Brain ◽

Zika Virus ◽

Brain Disorders ◽

Epigenetic Changes ◽

Zikv Infection ◽

Human Neural Stem Cells ◽

Neural Genes

Scientific research on human neural stem cells and cerebral organoids has confirmed the congenital neurotropic and neurodestructive nature of the Zika virus. However, the extent to which prenatal ZIKV infection is associated with more subtle brain alterations, such as epigenetic changes, remains ill defined. Here, we address the question of whether ZIKV infection induces DNA methylation changes with the potential to cause brain disorders later in life.

Download Full-text

Loss of postnatal quiescence of neural stem cells through mTOR activation upon genetic removal of cysteine string protein-α

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1817183116 ◽

2019 ◽

Vol 116 (16) ◽

pp. 8000-8009 ◽

Cited By ~ 6

Author(s):

Jose L. Nieto-González ◽

Leonardo Gómez-Sánchez ◽

Fabiola Mavillard ◽

Pedro Linares-Clemente ◽

María C. Rivero ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Neural Stem Cells ◽

Neural Stem Cell ◽

Molecular Mechanisms ◽

Radial Glia ◽

Brain Dysfunction ◽

Mtor Signaling ◽

Cysteine String Protein ◽

Newborn Neurons

Neural stem cells continuously generate newborn neurons that integrate into and modify neural circuitry in the adult hippocampus. The molecular mechanisms that regulate or perturb neural stem cell proliferation and differentiation, however, remain poorly understood. Here, we have found that mouse hippocampal radial glia-like (RGL) neural stem cells express the synaptic cochaperone cysteine string protein-α (CSP-α). Remarkably, in CSP-α knockout mice, RGL stem cells lose quiescence postnatally and enter into a high-proliferation regime that increases the production of neural intermediate progenitor cells, thereby exhausting the hippocampal neural stem cell pool. In cell culture, stem cells in hippocampal neurospheres display alterations in proliferation for which hyperactivation of the mechanistic target of rapamycin (mTOR) signaling pathway is the primary cause of neurogenesis deregulation in the absence of CSP-α. In addition, RGL cells lose quiescence upon specific conditional targeting of CSP-α in adult neural stem cells. Our findings demonstrate an unanticipated cell-autonomic and circuit-independent disruption of postnatal neurogenesis in the absence of CSP-α and highlight a direct or indirect CSP-α/mTOR signaling interaction that may underlie molecular mechanisms of brain dysfunction and neurodegeneration.

Download Full-text

Zika Virus Impairs Neurogenesis and Synaptogenesis Pathways in Human Neural Stem Cells and Neurons

Frontiers in Cellular Neuroscience ◽

10.3389/fncel.2019.00064 ◽

2019 ◽

Vol 13 ◽

Cited By ~ 12

Author(s):

Livia Rosa-Fernandes ◽

Fernanda Rodrigues Cugola ◽

Fabiele Baldino Russo ◽

Rebeca Kawahara ◽

Caio Cesar de Melo Freire ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Zika Virus ◽

Human Neural Stem Cells

Download Full-text

Expression Analysis Highlights AXL as a Candidate Zika Virus Entry Receptor in Neural Stem Cells

Cell Stem Cell ◽

10.1016/j.stem.2016.03.012 ◽

2016 ◽

Vol 18 (5) ◽

pp. 591-596 ◽

Cited By ~ 326

Author(s):

Tomasz J. Nowakowski ◽

Alex A. Pollen ◽

Elizabeth Di Lullo ◽

Carmen Sandoval-Espinosa ◽

Marina Bershteyn ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Expression Analysis ◽

Zika Virus ◽

Virus Entry ◽

Entry Receptor

Download Full-text

Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

10.1101/533497 ◽

2019 ◽

Author(s):

Jean A. Bernatchez ◽

Michael Coste ◽

Sungjun Beck ◽

Grace A. Wells ◽

Lucas A. Luna ◽

...

Keyword(s):

Stem Cells ◽

Neural Stem Cells ◽

Nucleoside Analogue ◽

Zika Virus ◽

Active Metabolite ◽

Cytopathic Effect ◽

Cell Model ◽

Strong Activity ◽

Human Neural Stem Cells ◽

Neurodevelopmental Impairment

AbstractZika virus (ZIKV), an emerging flavivirus which causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome, continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Conversion of the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine to a 2-(methylthio)ethyl phosphoramidate completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. Molecular superpositioning revealed different orientations of residues opposite the 2′-fluoro group of sofosbuvir. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

Download Full-text

Understanding microcephaly through the study of centrosome regulation in Drosophila neural stem cells

Biochemical Society Transactions ◽

10.1042/bst20200261 ◽

2020 ◽

Vol 48 (5) ◽

pp. 2101-2115

Author(s):

Beverly V. Robinson ◽

Victor Faundez ◽

Dorothy A. Lerit

Keyword(s):

Stem Cells ◽

Drosophila Melanogaster ◽

Cell Division ◽

Virus Infection ◽

Neural Stem Cells ◽

Head Circumference ◽

Zika Virus ◽

Asymmetric Cell Division ◽

Significant Proportion ◽

Neuronal Progenitors

Microcephaly is a rare, yet devastating, neurodevelopmental condition caused by genetic or environmental insults, such as the Zika virus infection. Microcephaly manifests with a severely reduced head circumference. Among the known heritable microcephaly genes, a significant proportion are annotated with centrosome-related ontologies. Centrosomes are microtubule-organizing centers, and they play fundamental roles in the proliferation of the neuronal progenitors, the neural stem cells (NSCs), which undergo repeated rounds of asymmetric cell division to drive neurogenesis and brain development. Many of the genes, pathways, and developmental paradigms that dictate NSC development in humans are conserved in Drosophila melanogaster. As such, studies of Drosophila NSCs lend invaluable insights into centrosome function within NSCs and help inform the pathophysiology of human microcephaly. This mini-review will briefly survey causative links between deregulated centrosome functions and microcephaly with particular emphasis on insights learned from Drosophila NSCs.

Download Full-text

Zika virus impairs growth in human neurospheres and brain organoids

10.7287/peerj.preprints.1817v2 ◽

2016 ◽

Cited By ~ 1

Author(s):

Patricia P Garcez ◽

Erick C Loiola ◽

Rodrigo F Madeiro da Costa ◽

Luiza Higa ◽

Pablo Trindade ◽

...

Keyword(s):

Electron Microscopy ◽

Stem Cells ◽

Neural Stem Cells ◽

Human Brain ◽

Brain Development ◽

Zika Virus ◽

Brain Cells ◽

Zikv Infection ◽

Human Neural Stem Cells ◽

Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

Download Full-text