EXTRACELLULAR MATRIX DEPLETION AMELIORATES NEUROMELANIN-INDUCED DOPAMINERGIC NEURODEGENERATION IN MICE

The extracellular matrix (ECM) of the brain plays a dual structural and signalling role, regulating extracellular diffusion and modulating glial cell function, thereby influencing both the clearance of toxic molecules and neuroinflammation, processes critical in Parkinson’s disease (PD). We previously demonstrated in mice that manipulation of the ECM-microglia axis ameliorates Lewy body-induced neurodegeneration. Here we focus on the tyrosinase overexpression model in mice (AAV-hTyr), which recapitulates the accumulation of neuromelanin (NM) observed in humans, a process that contributes to dopaminergic cell death. We used ex vivo and in vivo paradigms to characterize dopaminergic neurodegeneration, eNM clearance and microglia state in response to ECM manipulation. We found that eNM dynamics were altered in AAV-hTyr-injected mice following ECM or microglia manipulation. Chronic ECM depletion or fragmentation with 4-methylumbelliferone (4-MU) and hyaluronidase, respectively, ameliorated pathological process by reducing dopaminergic cell loss and decreasing eNM levels, likely through enhanced diffusion and microglial phagocytosis. Longitudinal time-lapse imaging in rat organotypic slices infected with AAV-hTyr or treated with purified NM allowed us to track microglial clearance of NM and monitor neuronal death over time. These findings shed light on non-neuronal mechanisms underlying NM-induced pathology and highlight the ECM-microglia axis as a potential therapeutic target for PD.