Objective: To investigate the interaction between neuromelanin (NM) and microglia in Parkinsons’s Disease (PD) using human post-mortem midbrain tissue and induced pluripotent stem cell (iPSC) derived microglial models from PD patients and healthy individuals.

Background: PD is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra (SN). DA neurons contain high levels of NM, a by-product of DA oxidation. Although NM may exert neuroprotective functions, it accumulates with age, increases DA neuron vulnerability to stress and may contribute to neurodegeneration. Following DA neuron death, NM is released in the extracellular space in the form of particles. Microglia, the resident immune cells of the brain, oversee homeostasis in the brain and are highly sensitive to environmental changes. NM particles may act as a sustained inflammatory stimulus, maintaining microglia in a prolonged activation. Chronic microglial activation can compromise neuronal viability leading to further release of NM particles and creating a vicious cycle.

Method: NM, microglia and DA neurons spatial distribution was first assessed in human post-mortem tissue using high-content imaging. The interaction between NM and microglia will be further investigated in tissue using spatial transcriptomics. In parallel, following a well-established protocol, microglia will be generated from PD patient-derived iPSCs and treated with NM, followed by the assessment of morphological changes and phagocytic uptake.

Results: Image analysis of midbrain tissue revealed a more amoeboid morphology of microglia near NM particles, indicative of a reactive phenotype. These findings suggest a potential link between NM particles and microglial activation in the SN. As a next step spatial transcriptomics analysis will be performed to identify inflammatory pathways associated with NM-interacting microglia. In addition, we plan to expose iPSC-derived patient microglia to NM to functionally validate key signaling molecules mediating NM-induced inflammation in PD.

Conclusion: Taken together, our findings show that NM-surrounded microglia acquire a reactive phenotype and may contribute to neuroinflammation and neurodegeneration in PD. Building on these results and ongoing assays, this study aims to uncover molecular pathways underlying NM-driven neuroinflammation in PD and to identify potential targets for therapeutic intervention.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/extracellular-neuromelanin-promotes-microglial-reactivity-in-parkinsons-disease/