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

• Published in: Biochemistry (Moscow) 2024-07, Vol.89 (7), p.1300-1312
• Main Authors: Bezrukova, Anastasia I., Basharova, Katerina S., Baydakova, Galina V., Zakharova, Ekaterina Y., N. Pchelina, Sofya, Usenko, Tatiana S.
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Biochemistry; Biomedical and Life Sciences; Biomedicine; Bioorganic Chemistry; Blood; Cell death; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzymatic activity; Enzymes; Glucosylceramidase; Glucosylceramidase - antagonists & inhibitors; Glucosylceramidase - metabolism; Humans; Kinases; Life Sciences; Lysosomes - metabolism; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Microbiology; Molecular modelling; Monocytes; Movement disorders; Mutation; Naphthyridines; Neuroblastoma; Neuroblastoma - drug therapy; Neuroblastoma - metabolism; Neuroblastoma - pathology; Neurodegeneration; Neurodegenerative diseases; Neuroprotection; Parkinson Disease - drug therapy; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson's disease; Pathogenesis; Peripheral blood; Phosphorylation; Protein kinase C; Proteins; Risk factors; Synuclein; Therapy; TOR protein; TOR Serine-Threonine Kinases - antagonists & inhibitors; TOR Serine-Threonine Kinases - metabolism
• ISSN: 0006-2979; 1608-3040; 1608-3040
• DOI: 10.1134/S0006297924070113

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.