Oligomeric α-synuclein and glucocerebrosidase activity levels in GBA-associated Parkinson’s disease

• DOI: 10.1016/j.neulet.2016.10.039
• Publication Date: 2016-10-22T11:15:53Z
• Authors: S. Pchelina; A. Emelyanov; G. Baydakova; P. Andoskin; K. Senkevich; M. Nikolaev; I. Miliukhina; A. Yakimovskii; A. Timofeeva; E. Fedotova; N. Abramycheva; T. Usenko; D. Kulabukhova; A. Lavrinova; A. Kopytova; L. Garaeva; E. Nuzhnyi; S. Illarioshkin; E. Zakharova
• Keywords: Male; 0301 basic medicine; Parkinson Disease; Middle Aged; 3. Good health; Protein Aggregates; 03 medical and health sciences; Case-Control Studies; Mutation; alpha-Synuclein; Glucosylceramidase; Humans; Female; Aged

Alpha-synuclein oligomerization plays a key role in the development of Parkinson's disease (PD). Being the most common genetic contributor to PD, glucocerebrosidase 1 (GBA) mutations have been associated with decreased GBA enzymatic activity in PD patients with mutations in the GBA gene (GBA-PD). However, it is unknown whether the activities of other lysosomal hydrolases are being altered in GBA-PD patients and are accompanied by an increase in alpha-synuclein oligomerization. The aim of our study was to estimate GBA enzymatic activity as well as the activities of five other lysosomal hydrolases (galactocerebrosidase, alpha-glucosidase, alpha-galactosidase, sphingomyelinase, alpha-iduronidase) in dried blood spots with assessing plasma oligomeric alpha-synuclein levels in sporadic PD (sPD) patients, in GBA-PD patients and in controls. GBA enzymatic activity and plasma oligomeric alpha-synuclein levels were assessed in sPD patients (N=84), in GBA-PD patients (N=21) and controls (N=62) by LC-MS/MS and ELISA methods accordingly. GBA-PD patients showed lower GBA enzymatic activity compared to controls (p=0.001) and to sPD (p=0.0001). We also found the reduction of GLA enzymatic activity (but not of other lysosomal hydrolases) in GBA-PD (p=0.001). At the same time plasma oligomeric alpha-synuclein levels were increased in GBA-PD group compared to sPD and controls (p=0.002 and p<0.0001, respectively). Our results suggest that the decrease in enzymatic activity of lysosomal hydrolases in GBA mutation carriers may contribute to PD pathogenesis by increasing the level of neurotoxic oligomeric alpha-synuclein species.