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-syn tot , α-syn olig ) 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-syn olig 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-syn olig 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.