Strain-Specific Reduction of Ndel1 Enzymatic Activity During Early Zika Virus Infection in the Neonatal Brain

<title>Abstract</title> <p> Zika virus (ZIKV) infection during early development is associated with severe neurodevelopmental impairment, including congenital microcephaly, yet the molecular mechanisms linking viral exposure to neuronal dysfunction remain incompletely understood. Ndel1 (nudE neurodevelopment protein 1 like 1) is an oligopeptidase critically involved in neuronal migration, neurite outgrowth, and cytoskeletal dynamics, processes essential for proper brain development. Building on previous observations that Ndel1 enzymatic activity is reduced in ZIKV-infected embryonic and neonatal brains, we investigated whether this modulation represents a conserved host response or a strain-specific molecular effect. Using a neonatal intracerebroventricular infection model in Swiss mice at postnatal day 0, we compared the effects of a Brazilian ZIKV strain (ZIKV ^BR ), an African lineage strain (ZIKV ^AF ), and dengue virus (DENV) on Ndel1 regulation in the brain. We found that Ndel1 enzymatic activity was significantly reduced at early post-infection time points (P3 and P7) exclusively in ZIKV ^BR -infected animals, whereas ZIKV ^AF and DENV did not alter enzyme activity relative to controls. Notably, this reduction occurred in the absence of changes in Ndel1 mRNA expression, indicating a post-transcriptional or functional mechanism of regulation. Although both ZIKV strains induced robust inflammatory gene expression, only ZIKV ^BR infection resulted in decreased Ndel1 activity, dissociating neuroinflammatory signaling from enzymatic modulation. Importantly, this strain-specific reduction parallels the unique capacity of ZIKV ^BR to induce microcephaly and supports Ndel1 dysfunction as an early molecular event associated with neurodevelopmental impairment. Together, these findings identify a virus- and strain-specific regulation of a key neuronal enzyme and provide mechanistic insight into the molecular basis of ZIKV ^BR -associated neurodevelopmental outcomes. </p>