Phosphorylated α-synuclein in Parkinson’s disease: correlation depends on disease severity

• DOI: 10.1186/s40478-015-0185-3
• Publication Date: 2015-01-30T14:43:32Z
• Authors: Tessandra Stewart; Vesna Sossi; Jan O Aasly; Zbigniew K Wszolek; Ryan J Uitti; Kazuko Hasegawa; Teruo Yokoyama; Cyrus P Zabetian; James B Leverenz; Alexander Jon Sto...; Yu Wang; Carmen Ginghina; Changqin Liu; Kevin C Cain; Peggy Auinger; Un Jung Kang; Poul Henning Jensen; Min Shi; Jing Zhang
• Keywords: Male; DATATOP; Time Factors; Statistics as Topic; 610; Protein Serine-Threonine Kinases; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; Severity of Illness Index; Cohort Studies; α-synuclein; Humans; Phosphorylation; Aged; Research; Parkinson Disease; Biomarker; Middle Aged; Protein-Serine-Threonine Kinases; 3. Good health; Cerebrospinal fluid; Cross-Sectional Studies; ROC Curve; Positron-Emission Tomography; Mutation; Parkinson’s disease; Disease Progression; alpha-Synuclein; Female; Biomarkers

Introduction: α-Synuclein (α-syn) is a key protein in Parkinson’s disease (PD), and one of its phosphorylated forms, pS129, is higher in PD patients than healthy controls. However, few studies have examined its levels in longitudinally collected cerebrospinal fluid (CSF) or in preclinical cases. In this study, CSF and clinical data were contributed by >300 subjects from three cohorts (the longitudinal DATATOP cohort, a large cross-sectional cohort, and a cohort of LRRK2 mutation carriers). Results Consistent with our previous observation that CSF pS129 positively correlated with Unified Parkinson’s Disease Rating Scale (UPDRS) scores, CSF pS129 in the DATATOP cohort increased over approximately two years of disease progression (mean change 5.60 pg/ml, p = 0.050). Intriguingly, in the DATATOP cohort, pS129 negatively correlated with UPDRS scores at the baseline (R = −0.244, p = 0.017), but not final point, suggesting that this association may depend on disease stage. Reanalysis of our previous cohort with stratification by PD stage, and addition of a cohort of LRRK2 mutation carriers with very early/preclinical PD, supported the idea that the relationship between CSF pS129 and disease severity over a wider range of PD stages might be represented with a U-shaped curve, in which lower pS129 levels correlated with worse clinical condition at early stages, but better condition at later stages. Conclusion The observation of a negative-to-positive transition of correlation of pS129 to disease severity as PD progresses could have profound impact on how pS129 is used as a biomarker clinically as well as in modeling PD experimentally.