Increased serum neurodevelopmental biomarker Ndel1 activity in medicated patients with depression is associated with reduced neurite density and neuronal viability independently of intracellular Ndel1 activity.

Depression is a leading cause of global disability, yet its biological mechanisms remain elusive, limiting therapeutic efficacy. We investigated Ndel1 oligopeptidase (NudE Neurodevelopment Protein 1 Like 1), a neurodevelopmental enzyme involved in neuronal migration and brain morphology with neuropeptidase activity, as a potential biomarker in major depressive disorder/unipolar depression (MDD/UD) or bipolar depression (BD). Serum Ndel1 activity was significantly elevated in both MDD/UD and BD compared to age- and sex-matched healthy control (HC). In vitro assays revealed that while psychotropics and patient serum both reduced neurite density - indicating circulating neurotoxic factors - intracellular responses differed. Indeed, only MDD/UD serum upregulated neuronal intracellular Ndel1 (iNdel1) activity, suggesting a disorder-specific mechanism against serum-induced neuronal stress evidenced by decreased neuronal cell viability. Additionally, we identified distinct immune signatures since sera from both disorders activated human Toll-like receptor 3 (TLR3), while TLR4 activation was exclusive to MDD/UD serum. These findings support the potential of Ndel1 as a peripheral biomarker candidate of neuronal injury, and propose TLR profiles as tools for differential diagnosis, strengthening the rationale for mechanism-based neuroimmune therapeutics for depression. Furthermore, a possible link between specific immune activation and Ndel1 activity modulation in neurons underscores a broader connection between the immune system and the cytoskeletal dynamics, while integrating the pharmacological response and neuronal structural morphology.