Assessing the role of Ndel1 oligopeptidase activity in congenital Zika syndrome: Potential predictor of congenital syndrome endophenotype and treatment response

• Published in: Journal of neurochemistry Vol. 166; no. 4; pp. 763 - 776
• Main Authors: Christoff, Raissa R., Nani, João V., Lessa, Gabriel, Rabello, Tailene, Rossi, Atila D., Krenn, Veronica, Higa, Luiza M., Tanuri, Amilcar, Garcez, Patricia P., Hayashi, Mirian A. F.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-08-2023
• Subjects: Animal models; Animals; Biomarkers; Birth defects; Brain; Brain injury; Cerebral cortex; Cognitive ability; Congenital defects; congenital zika virus syndrome; Corpus callosum; Deregulation; Developmental stages; Disease transmission; Embryos; Forebrain; Head injuries; Infections; Inoculum; Interferon; Microcephaly; Microencephaly; Molecular modelling; Ndel1; Offspring; Oligopeptidase; Risk factors; Vector-borne diseases; Zika virus; microcephaly; oligopeptidase; congenital zika virus syndrome; zika virus; Ndel1
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.15918

Maternal infections are among the main risk factors for cognitive impairments in the offspring. Zika virus (ZIKV) can be transmitted vertically, causing a set of heterogeneous birth defects, such as microcephaly, ventriculomegaly and corpus callosum dysgenesis. Nuclear distribution element like‐1 (Ndel1) oligopeptidase controls crucial aspects of cerebral cortex development underlying cortical malformations. Here, we examine Ndel1 activity in an animal model for ZIKV infection, which was associated with deregulated corticogenesis. We observed here a reduction in Ndel1 activity in the forebrain associated with the congenital syndrome induced by ZIKV isolates, in an in utero and postnatal injections of different inoculum doses in mice models. In addition, we observed a strong correlation between Ndel1 activity and brain size of animals infected by ZIKV, suggesting the potential of this measure as a biomarker for microcephaly. More importantly, the increase of interferon (IFN)‐beta signaling, which was used to rescue the ZIKV infection outcomes, also recovered Ndel1 activity to levels similar to those of uninfected healthy control mice, but with no influence on Ndel1 activity in uninfected healthy control animals. Taken together, we demonstrate for the first time here an association of corticogenesis impairments determined by ZIKV infection and the modulation of Ndel1 activity. Although further studies are still necessary to clarify the possible role(s) of Ndel1 activity in the molecular mechanism(s) underlying the congenital syndrome induced by ZIKV, we suggest here the potential of monitoring the Ndel1 activity to predict this pathological condition at early stages of embryos or offspring development, during while the currently employed methods are unable to detect impaired corticogenesis leading to microcephaly. Ndel1 activity may also be possibly used to follow up the positive response to the treatment, such as that employing the IFN‐beta that is able to rescue the ZIKV‐induced brain injury.
Nuclear distribution element like‐1 (Ndel1) oligopeptidase participates in several neurodevelopmental steps. Ndel1 activity was investigated in a microcephaly mouse model caused by Zika Virus (ZIKV) infection. A reduction of Ndel1 activity is observed in the ZIKV‐infected mice forebrain regardless of age, route of infection or titer. Also, there is a strong correlation between Ndel1 activity and the ZIKV‐infected brain size. ZIKV‐infected brain size and NDEL1 activity were rescued after Interferon‐beta (IFNβ) administration.