title: Oligomeric α-synuclein and glucocerebrosidase activity levels in GBA-associated Parkinson's disease.
abstract: 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.
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia; First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia; St. Petersburg Academic University-Nanothecnology Research and Education Centre, RAS, St. Petersburg, Russia; Institute of Experimental Medicine, St. Petersburg, Russia. Electronic address: sopchelina@hotmail.com.
authors: S
authors: S
authors: Pchelina
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia; First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia; St. Petersburg Academic University-Nanothecnology Research and Education Centre, RAS, St. Petersburg, Russia.
authors: A
authors: A
authors: Emelyanov
authors: Research Center of Medical Genetics, Moscow, Russia.
authors: G
authors: G
authors: Baydakova
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia.
authors: P
authors: P
authors: Andoskin
authors: First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia; Institute of Experimental Medicine, St. Petersburg, Russia.
authors: K
authors: K
authors: Senkevich
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia; First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.
authors: M
authors: M
authors: Nikolaev
authors: First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia; Institute of Experimental Medicine, St. Petersburg, Russia.
authors: I
authors: I
authors: Miliukhina
authors: First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.
authors: A
authors: A
authors: Yakimovskii
authors: First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.
authors: A
authors: A
authors: Timofeeva
authors: Research Centre of Neurology, Moscow, Russia.
authors: E
authors: E
authors: Fedotova
authors: Research Centre of Neurology, Moscow, Russia.
authors: N
authors: N
authors: Abramycheva
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia; First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia.
authors: T
authors: T
authors: Usenko
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia.
authors: D
authors: D
authors: Kulabukhova
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia.
authors: A
authors: A
authors: Lavrinova
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia.
authors: A
authors: A
authors: Kopytova
authors: Petersburg Nuclear Physics Institute, St. Petersburg, Russia.
authors: L
authors: L
authors: Garaeva
authors: First Pavlov State Medical University of St. Petersburg, St. Petersburg, Russia; Research Centre of Neurology, Moscow, Russia.
authors: E
authors: E
authors: Nuzhnyi
authors: Research Centre of Neurology, Moscow, Russia.
authors: S
authors: S
authors: Illarioshkin
authors: Research Center of Medical Genetics, Moscow, Russia.
authors: E
authors: E
authors: Zakharova
mesh_terms: D000368:Aged; D016022:Case-Control Studies; D005260:Female; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D066329:Protein Aggregates; D051844:alpha-Synuclein / Q000097:blood*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D005962:Glucosylceramidase
keywords: Alpha-synuclein aggregation; Enzymatic activity; GBA mutations; Parkinson’s disease