Russian Journal of PhysiologyRussian Journal of PhysiologyРоссийский физиологический журнал им. И.М. Сеченова0869-81392658-655XThe Russian Academy of Sciences68740010.31857/S0869813925060018TFSVTFREVIEWОБЗОРНЫЕ СТАТЬИReview ArticleSting signaling pathway as a target for neuroprotective therapy in Parkinson's diseaseСигнальный путь Sting как мишень нейропротекторной терапии при болезни ПаркинсонаUsenkoT. S.УсенкоТ. С.
Russian Federation
usenko_ts@pnpi.nrcki.ruPetersburg Nuclear Physics Institute, Kurchatov Institute National Research CenterПетербургский институт ядерной физики им. Б.П. Константинова НИЦ “Курчатовский институт”Pavlov First Saint Petersburg State Medical UniversityПервый Санкт-Петербургский государственный медицинский университет им. акад. И.П. Павлова1506202511168218461307202513072025Copyright ©; 2025, Russian Academy of SciencesCopyright ©; 2025, Российская академия наук2025Russian Academy of SciencesРоссийская академия наукhttps://journals.eco-vector.com/0869-8139/article/view/687400

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.

Болезнь Паркинсона (БП) – одно из наиболее распространенных нейродегенеративных заболеваний, характеризующееся гибелью дофаминергических нейронов и накоплением агрегатов белка альфа-синуклеина. Молекулярные механизмы, лежащие в основе патогенеза БП, остаются неизвестными, и, как следствие, на сегодняшний день не существует нейропротекторной терапии. Однако недавнее исследование выявило связь между накоплением и агрегацией белка альфа-синуклеина, активацией ответа интерферонов I типа в микроглии и последующей нейродегенерацией. STING (Stimulator of interferon genes, стимулятор генов интерферона) – ключевой регулятор врожденного иммунитета, контролирующий продукцию интерферонов I типа и развитие воспалительных реакций. Его активация инициирует сигнальные каскады, регулирующие иммунные ответы, механизмы клеточной гибели и аутофагию. В контексте БП гиперактивация STING может способствовать прогрессированию нейровоспаления и последующей нейродегенерации. В связи с этим разработка ингибиторов STING, способных модулировать его активность, рассматривается как перспективное направление для терапии БП. Однако, учитывая многофункциональность STING в клетке, при разработке терапии БП на основе ингибирования STING необходимо учитывать баланс между его активностью и эффективностью действия. Такой баланс можно достичь при сочетанном применении ингибитора STING с другими соединениями, например, направленными на редукцию белка альфа-синуклеина. В данном обзоре рассматриваются структурные особенности и механизмы активации STING, его роль в регуляции клеточной гибели и аутофагии, а также потенциальные терапевтические стратегии ингибирования данного пути для разработки новых методов лечения БП, в частности БП, ассоциированной с мутациями в гене GBA1.

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