Dose-Dependent Alterations of Lysosomal Activity and Alpha-Synuclein in Peripheral Blood Monocyte-Derived Macrophages and SH-SY5Y Neuroblastoma Cell Line by upon Inhibition of MTOR Protein Kinase – Assessment of the Prospects of Parkinson’s Disease Therapy

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Anastasia I. Bezrukova^1,2,a*, Katerina S. Basharova¹, Galina V. Baydakova³, Ekaterina Y. Zakharova³, Sofya N. Pchelina^1,2, Tatiana S. Usenko^1,2

¹Konstantinov Petersburg Nuclear Physics Institute, National Research Centre “Kurchatov Institute”, 188300 Gatchina, Leningrad Region, Russia

²Pavlov First Saint Petersburg State Medical University, 197022 Saint Petersburg, Russia

³Research Center for Medical Genetics, 115522 Moscow, Russia

^* To whom correspondence should be addressed.

Received: March 25, 2024; Revised: May 22, 2024; Accepted: June 9, 2024

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To date, the molecular mechanisms of the common neurodegenerative disorder Parkinson’s disease (PD) are unknown and, as a result, there is no neuroprotective therapy that may stop or slow down the process of neuronal cell death. The aim of the current study was to evaluate the prospects of using the mTOR molecule as a potential target for PD therapy due to the dose-dependent effect of mTOR kinase activity inhibition on cellular parameters associated with, PD pathogenesis. The study used peripheral blood monocyte-derived macrophages and SH-SY5Y neuroblastoma cell line. As a result, we have for the first time showed that inhibition of mTOR by Torin1 only at a concentration of 100 nM affects the level of the lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene. Mutations in GBA1 are considered a high-risk factor for PD development. This concentration led a decrease in pathological phosphorylated alpha-synuclein (Ser129), an increase in its stable tetrameric form with no changes in the lysosomal enzyme activities and concentrations of lysosphingolipids. Our findings suggest that inhibition of the mTOR protein kinase could be a promising approach for developing therapies for PD, particularly for GBA1-associated PD.

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KEY WORDS: Parkinson’s disease, mTOR, Torin 1, alpha-synuclein, glucocerebrosidase, autophagy, lysosomal enzyme activity, lysosphingolipids

DOI: 10.1134/S0006297924070113

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