Objective: To evaluate alterations in the phosphorylated, oligomeric alpha-synuclein and GBA activity levels in plasma from patients with sporadic Parkinson’s disease (sPD), PD patients with L444P, N370P, E326K mutations in the GBA gene (mPD) and controls.

Background: Impaired metabolism of alpha-synuclein and its aggregation in neuronal cells are implicated in the pathogenesis of PD. It has been shown that phosphorylation of alpha-synuclein at Ser129 could promote its oligomerization in pheripheral tissues. Mutations in the gene encoding glucocerebrosidase (GBA) have been associated with PD in different ethnic populations. We hypothesized that the loss of enzyme activity due to mutations in the GBA gene, promotes accumulation of alpha-synuclein in the cell, resulting in the formation of its neurotoxic oligomeric forms.

Methods: Here we examined alterations in the phosphorylated, oligomeric alpha-synuclein and GBA activity levels in peripheral blood plasma from mPD patients (n=17), sPD patients (n=23) and controls (n=28). All subjects were residents of the North-Western region of Russia and ethnically matched. The level of oligomeric alpha-synuclein (pg/ml) were estimated in plasma by ELISA method (Human Alpha-Synuclein OLIGO kit (ajRoboscreen, Germany). GBA activity was measured in dry blood spot using tandem mass spectrometry. Phosphorylated alpha-synuclein level was assessed in extracted alpha-synuclein fraction from individual PD and control plasma samples by immunocapture on magnetic Dynabeads (Invitrogen, USA) by immunoblotting.

Results: The level of oligomeric alpha-synuclein in plasma was higher in mPD patients (median (min-max): 1,74 (0,48 – 1259,41)) than in sPD patients (0,42 (0,16 – 23,56))(p=0,005) and control subjects (0,48 (0,16 – 400,83)) (p=0,004). GBA activity was reduced in mPD patients (5,6 (1,76 – 15,78)) compared to sPD patients (n=20; 7,6 (3,91 – 13,01)) (p=0,04) and controls (10,35 (4,26 – 19,76)) (p=0,001). Reduced phosphorylated alpha-synuclein level was observed in mPD patients (n=8; mean±S.E.M: 0,88 ±0,07) compared to sPD (n=19; 1,12±0,07) (p=0,005) and controls (n=17; 1,19±0,07) (p=0,009).

Conclusions: Taken together our findings suppose that the high risk of GBA-associated PD could be linked with reduced GBA activity and increased oligomeric alpha-synuclein levels. (This research has been supported by RFBR grants (16-54-76009 ERA_a, 16-04-00764 A)).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/oligomeric-alpha-synuclein-and-glucocerebrosidase-activity-levels-in-gba-associated-parkinsons-disease/