Glucocerebrosidase dysfunction and alpha-synuclein accumulation - a pathophysiological duet in GBA-associated Parkinson's disease
https://doi.org/10.25557/2073-7998.2022.12.18-22
Abstract
Glucocerebrosidase (GCase) is a lysosomal enzyme encoded by the GBA gene, mutations in which are the most common genetic risk factor for Parkinson’s disease (PD). Homozygous carriage of mutations in the GBA gene leads to the development of Gaucher disease (GD). It has been shown that mutations in the GBA gene can affect the accumulation of alpha-synuclein protein. Its aggregation is currently considered as a key link in the pathogenesis of PD. In this study, we compared the enzymatic activity of GCase, the concentration of the HexSph enzyme substrate and the level of alpha-synuclein protein in the primary culture of macrophages of patients with GD, GBA-associated PD, asymptomatic carriers of mutation in the GBA gene and control group individuals in the presence of a selective GCase inhibitor conduritol-B-epoxide, as well as in the brain cells of model animals with lysosome dysfunction. As a result of the study conducted on the primary culture of macrophages, as well as on animal models, it was shown that lysosome dysfunction leads to decreased GCase activity and HexSph accumulation. In this study on model animals, we have shown for the first time the effect of GCase function inhibition on the oligomeric forms of alpha-synuclein accumulation.
About the Authors
M. A. Nikolaev
Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute»; Pavlov First Saint-Petersburg State Medical University
Russian Federation
Russian Federation
A. E. Kopytova
Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute»; Pavlov First Saint-Petersburg State Medical University
Russian Federation
Russian Federation
M. M. Rudenok
Institute of Molecular Genetics of National Research Centre «Kurchatov Institute»
Russian Federation
Russian Federation
A. D. Izyumchenko
Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute»
Russian Federation
Russian Federation
A. S. Jouravlev
Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute»
Russian Federation
Russian Federation
I. V. Miliukhina
Institute of the Human Brain RAS
Russian Federation
Russian Federation
G. V. Baydakova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
M. I. Shadrina
Institute of Molecular Genetics of National Research Centre «Kurchatov Institute»
Russian Federation
Russian Federation
E. Y. Zakharova
Research Centre for Medical Genetics
Russian Federation
Russian Federation
P. A. Slominsky
Institute of Molecular Genetics of National Research Centre «Kurchatov Institute»
Russian Federation
Russian Federation
A. K. Emelyanov
Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute»; Pavlov First Saint-Petersburg State Medical University
Russian Federation
Russian Federation
S. N. Pchelina
Petersburg Nuclear Physics Institute named by B.P. Konstantinov of National Research Centre «Kurchatov Institute»; Pavlov First Saint-Petersburg State Medical University
Russian Federation
Russian Federation
References
1. Gegg M.E., Verona G., Schapira A.V. Glucocerebrosidase deficiency promotes release of α-synuclein fibrils from cultured neurons. Human Molecular Genetics. 2020;29(10):1716-1728
2. Emelyanov A.K., Usenko T.S., Tesson C., et al. Mutation analysis of Parkinson’s disease genes in a Russian data set. Neurobiology of Aging. 2018;71:267.e7-267.e10
3. Do J., McKinney C., Sharma P., Sidransky E. Glucocerebrosidase and its relevance to Parkinson disease. Molecular Neurodegeneration. 2019;14(1)
4. Zunke F., Moise A.C., Belur N.R., et al. Reversible Conformational Conversion of α-Synuclein into Toxic Assemblies by Glucosylceramide. Neuron. 2018;97(1):92-107.e10
5. Mus L., Siani F., Giuliano C., et al. Development and biochemical characterization of a mouse model of Parkinson’s disease bearing defective glucocerebrosidase activity. Neurobiology of Disease. 2019;124:289-296
6. Brighina L., Prigione A., Begni B., Galbussera A., Andreoni S., Piolti R. et al. Lymphomonocyte alpha-synuclein levels in aging and in Parkinson disease. Neurobiology of Aging. 2010;31(5):884-885
Review
For citations:
Nikolaev M.A., Kopytova A.E., Rudenok M.M., Izyumchenko A.D., Jouravlev A.S., Miliukhina I.V., Baydakova G.V., Shadrina M.I., Zakharova E.Y., Slominsky P.A., Emelyanov A.K., Pchelina S.N. Glucocerebrosidase dysfunction and alpha-synuclein accumulation - a pathophysiological duet in GBA-associated Parkinson's disease. Medical Genetics. 2022;21(12):18-22. (In Russ.) https://doi.org/10.25557/2073-7998.2022.12.18-22
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