Mitochondrial dysfunction and neuroinflammation play major roles in Parkinson's disease (PD). Overactivation of the inflammasome (innate immune system receptor) signaling complex NLRP3 is suspected to contribute to dopaminergic neurodegeneration. The PD-associated proteins PINK1 and Parkin jointly regulate mitochondrial quality control pathways and have also been linked to innate immunity. Our preliminary studies suggest that Parkin deficiency and mitochondrial dysfunction work in concert to amplify NLRP3 activation in glial cells.
We hypothesize that mitochondrial dysfunction, caused or worsened by deficient PARK2/PARK6-dependent mitochondrial surveillance pathways, aggravates NLRP3-dependent inflammation, thereby putting dopaminergic neurons at risk. We propose to examine this interplay and its consequence in PINK1 and Parkin pre-clinical models.
We will investigate NLRP3 inflammasome-dependent responses in microglial cells in Parkin or PINK1-deficient pre-clinical models and evaluate the consequence of altered glial activation profiles on the survival of co-cultured naïve dopaminergic neurons. We will also explore the potential of rescue approaches based on NLRP3 modulators and mitochondrion-protective drugs. As a first step toward translation to the clinic, key observations will be validated in macrophages from PD participants with mutations in the Parkin gene. Finally, we will search for associations between variants in genes belonging to the NLRP3 inflammasome pathway and familial or sporadic forms of the disease.
Impact on Diagnosis/Treatment of Parkinson's disease:
We anticipate that targeting NLRP3 inflammasomes and/or mitochondria by therapeutic approaches will have beneficial effects in PINK1 and Parkin-deficient pre-clinical models. The NRLP3 inflammasome is a key target in inflammatory diseases and our study will help establish its relevance for PD.
Next Steps for Development:
The next step would be a more global analysis of aberrant NLRP3-dependent profiles in macrophages or monocyte-derived microglia from individuals with different familial and sporadic forms of PD to help stratify patients towards the development of personalized treatments.