Evaluating STING inhibition as a therapeutic approach to mitigate neurodegeneration in a preclinical model of Parkinson's disease.

• Applicant: Dr. Eva Szego, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2026
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 578901359

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease and affects millions of people worldwide. It is characterized by motor symptoms such as tremor, muscle rigidity and slowed movements. In the brain, the disease is marked by a progressive loss of dopaminergic neurons and by the accumulation of the protein alpha-synuclein in a misfolded form. Although the exact causes of PD remain unclear, many studies indicate that inflammatory processes in the brain play a central role in driving disease progression. One important pathway in this context is the STING pathway (“stimulator of interferon genes”). STING is activated when DNA appears in the cytoplasm of a cell, for example as a result of cellular stress or damage. In PD, misfolded alpha-synuclein can trigger such stress reactions, leading to STING activation. This, in turn, provokes an immune response within neurons, which is further amplified by glial cells. As a consequence, chronic inflammation develops that promotes further neuronal damage, creating a vicious cycle of protein accumulation, cell injury and immune activation.The aim of this project is to investigate whether pharmacological inhibition of STING can break this cycle and thereby slow the progression of Parkinson’s disease. To address this, I will use an established mouse model of alpha-synuclein pathology and apply compounds that block STING activity. The project will assess whether such inhibition can reduce protein aggregation, neuronal loss, and the associated motor impairments. It will also examine whether treatment remains effective in older animals or when initiated after neurodegeneration has already begun, reflecting the clinical situation of patients who are often diagnosed only after substantial disease progression. In addition, modern molecular approaches such as transcriptomics and molecular cartography will be employed to analyze how STING inhibition influences gene activity across different cell types and signaling pathways. Preliminary data from primary neuronal cultures already demonstrate that blocking STING protects against alpha-synuclein–induced damage. These findings strongly support the feasibility and translational potential of the planned experiments.Overall, this project will provide new insights into the role of STING signaling in Parkinson’s disease and evaluate the therapeutic potential of its inhibition as a disease-modifying approach. Since chronic inflammation is also a hallmark of other neurodegenerative diseases such as Alzheimer’s, the results may have broader implications beyond Parkinson’s disease.

• DFG Programme: Research Grants