SGK1 downregulation co-occurs with leukocyte oligomeric α-synuclein accumulation in Parkinson's disease

Background: Serum and glucocorticoid-inducible kinase 1 (SGK1) is a ubiquitous kinase with cytoprotective and immune-specific functions. Parkinson's disease (PD) animal models disclosed interactions between SGK1 and the critical pathogenic pathways of the disease, whereas human-based evidence is lacking. We investigated the SGK1 contribution to the biological dynamics of PD ex vivo, at immune and systemic level. Methods: Thirty-two well-phenotyped PD patients and 34 controls were enrolled. Peripheral blood mononuclear cells (PBMCs) and serum were obtained. PBMCs levels of SGK1, α-synuclein total and oligomeric forms (α-syntot, α-synolig) were measured by Western blot and ELISA, respectively. SGK1 levels were tested in the serum by ELISA. Group differences were assessed using age-adjusted, rank-based linear regression models; ROC analysis was performed using age-adjusted PBMC SGK1 residuals and a Youden-derived cutpoint; associations with clinical variables were tested using age-adjusted regressions. Results: PD PBMCs exhibited lower SGK1 (p < 0.001) and higher α-synolig levels than controls (p = 0.026). SGK1 serum levels were also lower in PD patients (p = 0.040). ROC analysis showed that PBMC SGK1 significantly discriminated PD from controls (AUC = 0.85,[95 % CI 0.75-0.95],p < 0.001). The optimal cutpoint yielded a sensitivity of 1.00 and a specificity of 0.60. No significant correlations were found between biological and clinical parameters. Conclusions: In PD patients, SGK1 was downregulated in both PBMCs and serum. Given the preliminary nature of these findings and the co-occurrence of α-synolig accumulation in leukocytes, common mechanistic pathways might be supposed, although pending confirmation. Nevertheless, SGK1 emerged as a potential target in PD, for both biomarker and therapeutic purposes.