STING Signaling Pathway as a Target for Neuroprotective Therapy in Parkinson’s Disease

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, so there are no effective neuroprotective therapies to date. Meanwhile, recent research has identified a link between alpha-synuclein accumulation and aggregation, activation of type I interferon microglial responses, and subsequent neurodegeneration. STING (Stimulator of Interferon Genes) is a key protein 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, given the multifunctionality of STING in cellular processes, a balance between its activity and therapeutic efficacy must be considered when developing PD therapies based on its inhibition. This balance could be achieved through combinatorial 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 its form associated with mutations in the GBA1 gene.