DIMETHYL FUMARATE MITIGATES ALPHA-SYNUCLEIN–INDUCED DEFECTS IN HUMAN 3D CORTICAL ORGANOIDS AND MOUSE MODELS OF SYNUCLEOPATHY

Synucleinopathies are neurodegenerative disorders characterized by the accumulation and spreading of misfolded alpha-synuclein (alpha-syn), leading to synaptic dysfunction, neuroinflammation, and progressive circuit alterations. Beyond neuronal pathology, increasing evidence indicates that glial cells actively contribute to disease progression, transitioning from supportive to dysfunctional states under pathological conditions. Although alpha-synucleinopathy has been extensively studied in genetic/animal models, its cellular and functional responses to aggregation – across distinct neural cell types – and their pharmacological modulation remain elusive. Here, we investigate the therapeutic potential of dimethyl fumarate (DMF), an FDA-approved drug with established immunomodulatory and antioxidant properties, as a repurposed strategy to counteract alpha-syn pathology. As a testing platform, we developed a human 3D cortical organoid model of synucleinopathy, in which endogenous alpha-syn aggregation is triggered by exposure to exogenous preformed fibrils (PFFs). PFFs treatment induced aggregation-associated alterations that prominently involved astrocytes, accompanied by increased oxidative stress and changes in network activity. These effects were attenuated with the in vitro administration of DMF. To comprehensively assess the effects of DMF on astrocyte and microglia populations, our analysis was extended to an established in vivo alpha-syn PFFs murine model. In line with the organoid findings, alpha-syn aggregation in vivo elicited selective astrocytic alterations, which were similarly mitigated by DMF. Together, our findings identify astrocytes as key mediators of alpha-syn–associated dysfunction and demonstrate that modulation of glial responses by DMF can attenuate aggregation-driven pathology across both human and murine models. This cross-model convergence supports DMF as a promising candidate for targeting disease-relevant mechanisms in alpha-synucleinopathies.