RUNX3 negatively regulates autophagic degradation of aggregated α-synuclein

Synucleinopathies are a group of neurodegenerative disorders characterized by the accumulation of α-synuclein (α-syn) aggregates in the brain. Elucidating the mechanisms of α-syn aggregation is important in understanding the pathogenesis of synucleinopathies. In this study, we identified Runt-related transcription factor 3 (RUNX3), a tumor suppressor gene that regulates autophagic activity, as a regulator of the level of intracellular α-syn aggregates. RUNX3 deficiency reduced the α-syn aggregates by inducing autophagic activity for the α-syn degradation, while the overexpression of RUNX3 resulted in an increased level of α-syn aggregates. Interestingly, treatment of cells with α-syn aggregates increased the expression of RUNX3, suggesting a feedback loop between α-syn aggregation and RUNX3 expression. Single nucleus RNA sequencing analysis revealed that RUNX3 expression was significantly increased in brains with multiple system atrophy. This further supports the feedback loop between RUNX3 and α-syn pathology, identifying RUNX3 as a potential therapeutic target for synucleinopathies.