Exploring the consequences of NLRP3 inflammasome pathway overactivation in Parkin-deficient models

Compelling evidence have highlighted the central role played by mitochondrial dysfunction and neuroinflammation in the susceptibility and progression of Parkinson’s disease (PD). Recent studies of my team focused on the protein Parkin, a major regulator of mitochondrial quality control, also associated with early-onset familial PD, demonstrating the presence of an exacerbated NLRP3 inflammasome response in microglia from Parkin-deficient mice. My research question was to explore how abnormal microglial responses in the context of Parkin-deficiency, and the associated exacerbation of the NLRP3 inflammasome pathway, affect dopaminergic neuron functionality and survival, whose death is the major hallmark in PD. I set up a mouse 2D and human 3D neuron-microglia culture model to explore the crosstalk between these two cell types. In the 2D system, following NLRP3 inflammasome stimulation on Prkn-/- microglia, DA neuron death was enhanced, a first evidence that Parkin-associated mitochondrial vulnerability impairs a physiological neuroprotective function of microglial cells. As regards the 3D system, I demonstrated the possibility to successfully integrate human monocyte-derived microglia-like cells (hMDMi) into human midbrain organoids. Overall, the data obtained provide a novel insight into the complex interplay between Parkin-related mitochondrial vulnerability and inflammatory pathways, validating microglial cells as central players in the neuro-inflammatory mechanisms of PD.