Objective: To assess the effects of combined inhibition of mTOR (autophagy regulator) and STING (inflammation regulator) on α-synuclein phosphorylation, tyrosine hydroxylase expression, and lysosphingolipid levels in macrophages and SH-SY5Y cells.

Background: Parkinson’s disease (PD) is a neurodegenerative disorder characterized by dopaminergic neuron loss and α-synuclein aggregation. GBA1-associated PD (GBA1-PD) is the most common genetic form of PD with a well-defined etiology, making it a prime target for developing disease-modifying therapies. GBA1 mutations impair glucocerebrosidase (GCase) activity, leading to lysosphingolipid accumulation, which may contribute to α-synuclein pathology. Our previous studies showed hyperactivation of the mTOR pathway and inflammation in primary macrophages from GBA1-PD patients by transcriptome analysis of cellular and animal models of PD with GCase dysfunction. mTOR regulates autophagy, while STING controls immune responses. Their combined inhibition may reduce pathogenic substrate accumulation and α-synuclein aggregation, offering a promising therapeutic strategy for GBA1-PD.

Method: Primary macrophage cultures were derived from peripheral blood mononuclear cells of 10 healthy volunteers (3 males, 7 females, mean age 27.3±9 years) and cultured in RPMI with M-CSF. Differentiated SH-SY5Y cells were also used. Cells were treated with mTOR inhibitor Torin 1 (100 nM) and STING inhibitor H-151 (1 μM) for 24 h. Western blotting assessed phosphorylated, oligomeric α-synuclein levelsn, tyrosine hydroxylase expression, as well as GCase activity and hexosylsphingosine (HexSph) levels were measured using HPLC-MS/MS.

Results: Neither Torin 1 nor H-151 alone significantly altered GCase activity or HexSph levels. However, combined inhibition of mTOR and STING resulted in a significant reduction in HexSph levels (p<0.05). Furthermore, this combination led to a notable decrease in α-synuclein phosphorylation, alongside an increase in tyrosine hydroxylase expression in SH-SY5Y cells (p<0.05).

Conclusion: Combined inhibition of STING and mTOR reduces lysosphingolipid accumulation and α-synuclein phosphorylation, while increasing tyrosine hydroxylase expression. These results highlight a promising therapeutic strategy for GBA1-PD, warranting further validation in patient-derived models. Supported by the Russian Science Foundation grant (24-25-00212).

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MDS Abstracts - https://www.mdsabstracts.org/abstract/targeting-inflammation-and-autophagy-a-dual-inhibition-strategy-to-reduce-%ce%b1-synuclein-pathology-in-gba1-associated-parkinsons-disease/