Sting signaling pathway as a target for neuroprotective therapy in Parkinson's disease

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders, characterized by the loss of dopaminergic neurons and the accumulation of aggregated alpha-synuclein protein. The molecular mechanisms underlying PD pathogenesis remain largely unknown, and as a result, no effective neuroprotective therapies are currently available. However, recent research has identified a link between alpha-synuclein accumulation and aggregation, activation of type I interferon responses in microglia, and subsequent neurodegeneration. STING (Stimulator of Interferon Genes) is a key regulator of innate immunity, responsible for the production of type I interferons and the orchestration of inflammatory responses. Upon activation, STING initiates signaling cascades that regulate immune responses, cell death mechanisms, and autophagy. In the context of PD, STING hyperactivation may contribute to the progression of neuroinflammation and associated neurodegeneration. Therefore, the development of STING inhibitors capable of modulating its activity is considered a promising therapeutic strategy for PD. At the same time, due to the multifunctional roles of STING in cellular processes, therapeutic approaches targeting STING in PD must carefully balance its activity and therapeutic efficacy. This balance may be achieved through combinatory treatments involving STING inhibitors and compounds that reduce alpha-synuclein levels. This review discusses the structural features and activation mechanisms of STING, its role in the regulation of cell death and autophagy, as well as potential therapeutic strategies targeting this pathway for the development of novel treatments for PD–particularly PD associated with mutations in the GBA1 gene.

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T. Usenko

Petersburg Nuclear Physics Institute, Kurchatov Institute National Research Center; Pavlov First Saint Petersburg State Medical University

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Email: usenko_ts@pnpi.nrcki.ru
Rússia, Gatchina; Saint Petersburg

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2. Fig. 1. Domain structure of the STING protein. N-terminal transmembrane domain (TMD) with four transmembrane helices (residues 1–138), cytosolic ligand binding domain (LBD, residues 139–336) and C-terminal domain (CTT, residues 337–379).

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3. Fig. 2. The mechanism of STING activation and its effect on the transcription of proinflammatory molecules. The release of mitochondrial DNA (mtDNA) into the cytoplasm due to mitochondrial damage serves as a signal for the activation of cGAS (cyclic GMP-AMP synthetase), which recognizes double-stranded DNA (mitochondrial, viral or bacterial). Activated cGAS synthesizes 2′,3′-cGAMP, a second messenger that binds to STING on the endoplasmic reticulum membrane. Binding of cGAMP causes conformational changes and oligomerization of STING, after which it is translocated to the Golgi apparatus. Here, STING activates TBK1 kinase, which phosphorylates STING and interferon regulatory factor 3 (IRF3). Phosphorylated IRF3 dimerizes and translocates to the nucleus, activating the synthesis of type I interferons. In parallel, STING stimulates NF-κB, enhancing the production of proinflammatory cytokines (TNF-α, IL-6) necessary for the immune response.

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4. Fig. 3. Regulation of autophagy processes by STING. STING activation leads to endoplasmic reticulum stress, subsequent mTOR inactivation and induction of canonical autophagy via the ULK1 complex. Activated STING promotes the recruitment of ATG16L1 to membrane structures, which ensures LC3 lipidation, which is important for the formation of autophagosomes. Alternatively, LC3 lipidation can occur in the endoplasmic reticulum and Golgi compartments with the participation of the WIPI2 and Atg5 complex, which leads to the induction of non-canonical autophagy. STING is involved in xenophagy induced by cytosolic pathogenic DNA, which is important for the elimination of viruses and bacteria. This process is triggered in response to the presence of cytosolic pathogenic DNA and is an important mechanism of cellular defense against infections.

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5. Fig. 4. Effect of STING H-151 and mTOR Torin 1 inhibition on primary culture of peripheral blood macrophages and SH-SY5Y neuroblastoma cell line. Combined use of STING H-151 and mTOR Torin 1 inhibitors resulted in decreased levels of neurotoxic forms of alpha-synuclein (oligomeric, phosphorylated Ser129) against the background of decreased concentration of the substrate of the lysosomal enzyme glucocerebrosidase (GCase) – hexosylsphingosine (HexSph), which belongs to the sphingolipid class. The efficiency of STING H-151 inhibition was assessed by the level of phosphorylated form TBK1, and mTOR Torin 1 inhibition – by the levels of phosphorylated forms of mTOR and RPS6.

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