Increased plasma oligomeric alpha-synuclein in patients with lysosomal storage diseases

Abstract

A link between lysosomal storage diseases (LSDs) and neurodegenerative disorders associated with accumulation of presynaptic protein alpha-synuclein has been shown. Particularly, Gaucher disease (GD) patients with a deficiency of the lysosomal enzyme glucocerebrosidase (GBA) and carriers of GBA mutations are at increased risk of Parkinson's disease (PD). It remains unclear whether this link is due to increased alpha-synuclein oligomerization. Here we show that level of oligomeric alpha-synuclein form, associated with PD development, is increased in plasma of GD patients (n=41, median=22.9pg/mL, range1.57-444.58pg/mL; controls (n=40, median=6.02pg/mL, range 1.05-103.14pg/mL, p<0.0001). This difference is absent in GD patients receiving enzyme replacement therapy (ERT) for more than 5 years. Moreover, the levels of alpha-synuclein oligomers in plasma are also higher in patients with other LSDs (Niemann-Pick type C, Krabbe disease, Wolman disease) compared to the median value in controls. Therefore, we suggest that mutations in the GBA gene and at least in several other LSDs genes may be associated with an increase in oligomeric alpha-synuclein in plasma. ERT applied for recovering of GBA functions in GD treatment might decrease formation of plasma oligomeric alpha-synuclein.

Keywords: Alpha-synuclein; Gaucher disease; Lysosomal storage diseases; Oligomerization; Parkinson's disease.