Whole Transcriptome Analysis of Substantia Nigra in Mice with MPTP-Induced Parkinsonism Bearing Defective Glucocerebrosidase Activity

Author:

Usenko Tatiana12ORCID,Bezrukova Anastasia12,Rudenok Margarita M.3,Basharova Katerina1,Shadrina Maria I.3,Slominsky Petr A.3,Zakharova Ekaterina4,Pchelina Sofya12

Affiliation:

1. Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Centre «Kurchatov Institute», 188300 Gatchina, Russia

2. Department of Molecular Genetic and Nanobiological Technologies, Pavlov First Saint-Petersburg State Medical University, 197022 Saint-Petersburg, Russia

3. Institute of Molecular Genetics, Russian Academy of Sciences, 123182 Moscow, Russia

4. Research Center for Medical Genetics, Laboratory of Hereditary Metabolic Diseases, 115522 Moscow, Russia

Abstract

Mutations in the GBA1 gene represent the major genetic risk factor for Parkinson’s disease (PD). The lysosomal enzyme beta-glucocerebrosidase (GCase) encoded by the GBA1 gene participates in both the endolysosomal pathway and the immune response. Disruption of these mechanisms is involved in PD pathogenesis. However, molecular mechanisms of PD associated with GBA1 mutations (GBA-PD) are unknown today in particular due to the partial penetrance of GBA1 variants in PD. The modifiers of GBA1 penetrance have not been elucidated. We characterized the transcriptomic profiles of cells from the substantia nigra (SN) of mice with co-injection with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and selective inhibitor of GCase activity (conduritol-β-epoxide, (CBE)) to mimic PD bearing GCase dysfunction (MPTP+CBE), mice treated with MPTP, mice treated with CBE and control mice treated with injection of sodium chloride (NaCl) (vehicle). Differential expression analysis, pathway enrichment analysis, and outlier detection were performed. Functional clustering of differentially represented transcripts revealed more processes associated with the functioning of neurogenesis, inflammation, apoptosis and autophagy in MPTP+CBE and MPTP mice than in vehicle mice, with a more pronounced alteration of autophagy processes in MPTP+CBE mice than in MPTP mice. The PI3K-Akt-mTOR signaling pathway may be considered a potential target for therapy in PD with GCase dysfunction.

Funder

Russian Science Foundation

Ministry of Science and Higher Education of the Russian Federation

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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