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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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 dose-dependent effect of mTOR kinase activity inhibition on cellular parameters, the alteration of which is associated with pathogenesis of the PD. The study was performed on peripheral blood monocyte-derived macrophages and SH-SY5Y neuroblastoma cell line. As a result, we have first 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 which are a high-risk factor for PD, and leads also to a decrease in pathological phosphorylated (Ser129) form of alpha-synuclein, an increase in its aggregation resistant tetrameric form in absence of the changes in lysosomal enzyme activities and lysosphingolipids concentrations. Inhibition of the protein kinase mTOR may be a promising approach for developing therapy for PD, in particular GBA1-associated PD.