Blood Plasma of Patients with Parkinson's Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity

A pathological hallmark of Parkinson's disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of alpha-synuclein (alpha-syn) aggregates, which involves release of alpha-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more alpha-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular alpha-syn. This was supported by the observations that phosphorylated alpha-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote alpha-syn phosphorylation and aggregation. We also analyzed neurotoxicity of alpha-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of alpha-syn aggregates via an alternative pathway and accelerate progression of PD.