Exploring immune-related pathways in familial forms of Parkinson’s disease

• Applicant: Michela Deleidi, Ph.D.
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Experimental Models for the Understanding of Nervous System Diseases
• Term: from 2021 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 490761034

Microglial activation is a feature of Parkinson’s disease (PD), but its actual contribution to disease remains poorly understood. Recent discoveries in familial PD linked to the PRKN and LRRK2 genes have provided support to a role of immunity in disease pathogenesis. Mutations in these genes lead to dysregulation of the interferon (IFN) and NLRP3 inflammasome pathways. We hypothesize that dysregulation of these pathways in microglia contributes to PD-related neurodegeneration. In this project, we will capitalize on our investments in the field of induced pluripotent stem cell (hiPSC) technologies, our long-standing and complementary expertise in the functional investigation of the LRRK2 and PRKN genes, and our access to biological material from PD patients carrying mutations in these genes, to generate innovative hiPSC-derived 2D triculture systems and microglia-enriched midbrain organoids, and interrogate the as yet poorly understood role of microglia in PD. Specifically, we propose to:1. Establish and characterize two complementary models of microglia-like cells, generated either from hiPSC or from human peripheral blood-derived monocytes, and determine how they are affected by PD-causing mutations in the PRKN and LRRK2 genes.2. Generate human hiPSC-derived tricultures and midbrain organoids incorporating these microglia-like cells, and determine how microglia affects its environment (i-e.- maturity and gene expression landscapes of astrocytes and neurons); and how the respective 2D and 3D environments affect in turn microglial functional and molecular characteristics.3. Recapitulate neuroinflammatory cascades relevant to LRRK2- and PRKN-linked PD, focusing on the IFN and NLRP3 inflammasome pathways, and determine their impact on neuroimmune interactions; and how they interplay with fundamental PD pathomechanisms, such as alpha-synucleinopathy and mitochondrial dysfunction.4. To dissect the relative contributions of LRRK2 and PRKN mutations, expressed selectively in microglia, on microglial properties, neuroimmune interactions and PD-relevant phenotypes.The project will deliver innovative human cell-based models for the investigation of cell-cell interactions in the normal and pathological brain. It will provide unprecedented insight into our understanding of neuroimmune crosstalk and the specific role of microglial cells in PD, and pave the way for discoveries potentially translatable to the clinic. Finally, it will create a synergistic collaborative framework that will strengthen academic visibility, leadership and competitiveness in the fields of iPSC technology and neurodegeneration in Europe.

• DFG Programme: Research Grants
• International Connection: France
• Cooperation Partner: Dr. Olga Corti