O-GLCNACYLATION AS A POTENTIAL BIOMARKER FOR PARKINSON'S DISEASE DIAGNOSIS

O-GlcNAcylation is a reversible, nutrient-sensitive post-translational modification (PTM) supporting neuronal health and function in neurodegenerative diseases including Parkinson’s disease (PD). We investigated NF-κB/c-Rel as a putative target of altered O-GlcNAcylation in PD. In line with previous evidence, the defective NF-κB/c-Rel is associated with a PD-like phenotype in mice, we found a reduced NF-κB/c-Rel DNA-binding activity both in PBMCs and substantia nigra from PD patients. As this phenomenon occurred with unchanged NF-κB/c-Rel protein levels, we focused on O-GlcNAcylation as a known PTM responsible for its DNA-binding activity. Western blot (WB) and immunoprecipitation assays confirmed reduced NF-κB/c-Rel O-GlcNAcylation levels in PBMCs isolated from fed PD patients.
In parallel, we detected a defect in global protein O-GlcNAcylation in patient-derived PBMCs and whole blood.
Upon exposure to high glucose and O-GlcNAcase (OGA) inhibitor, cultured PBMCs from healthy controls (HC) exhibited a significant increase in total O-GlcNAcylation, whereas PBMCs from PD failed to mount this adaptive response, as assessed by WB and ELISA. Moreover, similar alteration was detected in whole blood collected under fasting and postprandial conditions. Dot blot analysis revealed reduced O-GlcNAc levels in PD postprandial samples compared to HC. To investigate whether this reduced O-GlcNAcylation stems from altered regulation of O-GlcNAc cycling enzymes, we quantified the expression of O-GlcNAc transferase (OGT) and OGA by RT-qPCR. Notably, the OGT-to-OGA mRNA ratio was significantly decreased in PD PBMCs.
These findings suggest that defective O-GlcNAc process represents a systemic hallmark of PD and a source of accessible peripheral biomarkers for PD diagnosis.
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