Gene Expression of Lysosomal Membrane Proteins in Parkinson Disease, Associated with Mutations in the Glucocerebrosidase Gene (GBA)

Usenko, Tatiana; Tatiana, Shiryaeva; Bezrukova, Anastasia; Anastasia, I Bezrukova; Bogdanova, D.; Darya, A Bogdanova; Николаев, Михаил; Mikhail, A Nikolaev; Miliukhina, Irina; Irina, V Miliukhina; Gracheva, E.; Elizaveta, V Gracheva; Senkevich, K.; Konstantin, A Senkevich; Zakharova, Ekaterina; Yu., Zakharova Ekaterina; Anton, Emil; Anton, Kristin; Pchelina, Sofya; Sofya, N Pchelina

doi:10.25692/acen.2020.2.6

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“…Kuo and colleagues suggested that GCase that fails to fold in the ER is efficiently targeted to lysosomes by chaperone-mediated autophagy (CMA), but blocks the multimerization of LAMP2A, resulting in a disruption of proteostasis and α-synuclein accumulation [49]. In our previous study, we found a decrease in expression of the LAMP2 gene in CD45+ blood cells in GBA-PD and PD patients compared to controls, with a more pronounced decrease in LAMP2 expression in GBA-PD, supporting the role of the disruption of the autophagy-lysosome pathway in GCase dysfunction [50].…”

Section: Discussionmentioning

confidence: 71%

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

Usenko

Bezrukova

Rudenok

et al. 2023

IJMS

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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.

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Section: Discussionmentioning

confidence: 71%