Increased α-synuclein phosphorylation and oligomerization and altered enzymes in plasma of patients with Parkinson’s disease

• Published in: Neuroscience Vol. 567; pp. 28 - 36
• Main Authors: Yin, Na, Li, Pengjie, Li, Xuran, Li, Xin, Wang, Yiming, Yu, Xiaohan, Deng, Yeyun, Wang, Chaodong, Yu, Shun
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16.02.2025
• Subjects: Aged; alpha-Synuclein - blood; alpha-Synuclein - metabolism; Ceramides - blood; Enzyme; Female; Glucosylceramidase - blood; Humans; Male; Middle Aged; Oligomerization; Parkinson Disease - blood; Parkinson Disease - enzymology; Parkinson’s disease; Phosphorylation; Protein Phosphatase 2 - blood; Protein Serine-Threonine Kinases - blood; Protein Serine-Threonine Kinases - metabolism; α-synuclein; Phosphorylation; MoCA; H&Y stage; LRRK2; M-α-syn; pS-α-syn; AUC; SD; GRKs; L-DOPA; LEDD; α-synuclein; UPDRS III; O-α-syn; GCase; Oligomerization; Enzyme; PLK2; ROC; PP2A; LNs; SDS-PAGE; HAMD; PD; α-syn; GlcCer; HC; LBs; Parkinson’s disease; ELISA
• ISSN: 0306-4522; 1873-7544; 1873-7544
• DOI: 10.1016/j.neuroscience.2024.12.056

•PD plasma promotes α-syn phosphorylation and oligomerization.•α-syn phosphorylation and oligomerization rates are higher in PD than in HC plasma.•Levels of enzymes regulating α-syn phosphorylation is altered in PD plasma.•α-syn phosphorylation and oligomerization rates discriminate PD patients from HCs. The brain of patients with Parkinson’s disease (PD) was characterized by increased phosphorylation and oligomerization of α-synuclein (α-syn) and altered activity of enzymes regulating α-syn phosphorylation and oligomerization. Whether increased α-syn phosphorylation and oligomerization as well as related enzyme changes can be detected in the plasma of PD patients remains unclear. Here, we showed that human α-syn proteins incubated in PD plasma formed more oligomerized α-syn (O-α-syn) and phosphorylated α-syn (pS-α-syn) than those in healthy control (HC) plasma. Receiver operating characteristic (ROC) curve indicated that α-syn oligomerization rate and phosphorylation rate discriminated PD patients well from HC subjects. Moreover, they were both positively correlated with Hoehn and Yahr staging and polo-like kinase 2 (PLK2, an enzyme promoting α-syn phosphorylation) levels, and negatively correlated with protein phosphatase 2A levels (PP2A, an enzyme dephosphorylating α-syn) and glucocerebrosidase (GCase, an enzyme whose deficiency causes α-syn oligomerization) activity and ceramide (a product of GCase and a natural PP2A activator) levels. The above results suggest that increased α-syn oligomerization and phosphorylation rates and related enzyme changes can be detected in PD plasma and used to discriminate PD patients from HC subjects and predict PD progression.