N-terminal proVGF modifications related to Amyotrophic Lateral Sclerosis

Objective: Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder characterized by motor dysfunction, for which effective therapies and early diagnostic biomarkers remain limited. This study comprehensively investigated ALS-associated alterations in the N-terminal region of the proVGF precursor protein, evaluating their potential as novel diagnostic and prognostic biomarkers and exploring their precise correlations with clinical severity and plasma neurofilament light chain (NfL), an established indicator of neuroaxonal injury. Methods: N-terminal proVGF levels were quantified using a custom immunoassay using human plasma and lymphocytes as well as motor neuron-like NSC-34 cells subjected to oxidative stress. The clinical cohort comprised 49 ALS patients (28 early-stage, 21 advanced-stage) and 50 age-matched healthy controls. To assess disease specificity, plasma from patients with Parkinson's disease (PD, n = 50), idiopathic dystonia (n = 15), and idiopathic rapid eye movement (REM) sleep behavior disorder (iRBD, n = 21) was analyzed alongside respective age-matched healthy controls (n = 26, 8, and 20). Furthermore, plasma NfL levels were measured and directly correlated with N-terminal proVGF concentrations. Results: N-terminal proVGF levels were significantly increased in both plasma and lymphocytes during the early and advanced stages of ALS. Plasma NfL levels were concomitantly elevated across all ALS patients. In advanced-stage patients, N-terminal proVGF concentrations significantly correlated with both ALSFRS-R scores and NfL levels. No significant N-terminal proVGF alterations were observed in PD, iRBD, or dystonia cohorts. Oxidative stress similarly upregulated N-terminal proVGF levels in vitro within NSC-34 cells. Conclusion: Alterations of the N-terminal region of proVGF are specific to ALS, highlighting their dual value as diagnostic and prognostic biomarkers.