What question did this study set out to answer?

This research aims to explore the role of serum Ndel1 as a biomarker in depressive disorders and its relationship with neuronal health.

March 22, 2026Open Access

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

Key Points

This research aims to explore the role of serum Ndel1 as a biomarker in depressive disorders and its relationship with neuronal health.
Compared serum Ndel1 activity between patients with major depressive disorder, bipolar depression, and healthy controls.
Assessed neurite density and neuronal viability in vitro with patient serum and psychotropic medications.
Analyzed immune responses via Toll-like receptor activation in relation to serum samples from both disorders.
Serum Ndel1 activity was significantly higher in both major depressive disorder and bipolar depression than in healthy controls.
Reduction in neurite density correlated with elevated serum Ndel1 levels in both disorders.
Increased intracellular Ndel1 activity was observed only in major depressive disorder serum, indicating distinct mechanistic pathways.

Abstract

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. • Elevated serum Ndel1 in MDD/UD and BD was associated with reduced neurite density. • Only MDD/UD serum boosts neuronal intracellular Ndel1 activity, unlike BD. • MDD/UD and BD serum induces neurite loss via circulating cytotoxic factors. • TLR3 is activated in MDD/UD and BD, while TLR4 is exclusive to MDD/UD. • Ndel1 activity and TLR signaling together are promising biomarkers for depression stratification.

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

Key Points

Abstract

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