LRRK2-mutant microglia and neuromelanin synergize to drive dopaminergic neurodegeneration in an iPSC-based Parkinson's disease model
Por:
Blasco-Agell L, Marina Pons Espinal, Testa V, Roch G, Montero-Muñoz J, Fernández Carasa I, Baruffi V, Gonzalez-Sepulveda M, Richaud-Patin Y, Jimenez S, Cuadros T, Cladera-Sastre JM, Compte J, Manglano-Artuñedo Z, Ventura S, Juan-Otero M, Tolosa E, Raya A, Vila M and Consiglio A
Publicada:
12 ago 2025
Ahead of Print:
12 ago 2025
Resumen:
Parkinson's disease (PD) is a progressive, incurable neurodegenerative disorder characterized by the loss of neuromelanin (NM)-containing dopamine neurons (DAn) in the substantia nigra of the midbrain. Non-neuronal cells are increasingly recognized as contributors to PD. We generated human microglia-like cells (hMG) from induced pluripotent stem cells (iPSC) derived from patients with LRRK2 PD-causing mutations, gene-corrected isogenic controls, and healthy donors. While neither genotype induced neurodegeneration in healthy DAn, LRRK2 hMG become hyperreactive to LPS stimulation, exhibiting increased cytokine expression, reactive oxygen species, and phagocytosis. When exposed to NM-containing particles, but not alpha-synuclein fibrils, LRRK2 hMG trigger DAn degeneration, in a process that is prevented by pre-treatment with the immunomodulatory drug ivermectin. Finally, post-mortem analysis of midbrain tissue of LRRK2-PD patients show increased microglia activation around NM-containing neurons, confirming our in vitro findings. Overall, our work highlights NM-activated microglia's role in PD progression, and provides a model for testing therapeutic targets.
Filiaciones:
Blasco-Agell L:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Marina Pons Espinal:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Testa V:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Roch G:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
Montero-Muñoz J:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Fernández Carasa I:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Baruffi V:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Gonzalez-Sepulveda M:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
Richaud-Patin Y:
Regenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL), and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain
Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
Jimenez S:
Regenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL), and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain
Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
Cuadros T:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
Cladera-Sastre JM:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
Compte J:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
Manglano-Artuñedo Z:
Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i de Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain
Ventura S:
Institut de Biotecnologia i de Biomedicina and Departament de Bioquímica i de Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra (Barcelona), Spain
Hospital Universitari Parc Taulí, Institut d'Investigació i Innovació Parc Taulí (I3PT-CERCA), Universitat Autònoma de Barcelona, Sabadell, Spain
Juan-Otero M:
Immunology Department-CDB, Hospital Clinic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain
Tolosa E:
Department of Neurology, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Barcelona, Spain
Raya A:
Regenerative Medicine Program, Bellvitge Biomedical Research Institute (IDIBELL), and Program for Clinical Translation of Regenerative Medicine in Catalonia (P-CMRC), Hospital Duran i Reynals, Hospitalet de Llobregat, Barcelona, Spain
Centre for Networked Biomedical Research on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Madrid, Spain
Catalan Institution for research and Advanced Studies (ICREA), Barcelona, Spain
Vila M:
Neurodegenerative Diseases Research Group, Vall d'Hebron Research Institute (VHIR)-Network Center for Biomedical Research in Neurodegenerative Diseases (CIBERNED), Barcelona, Spain
Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, USA
Catalan Institution for research and Advanced Studies (ICREA), Barcelona, Spain
Department of Biochemistry and Molecular Biology, Neuroscience Institute, Autonomous University of Barcelona, Barcelona, Spain
Consiglio A:
Department of Pathology and Experimental Therapeutics, Bellvitge University Hospital-IDIBELL, Hospitalet de Llobregat, Spain
Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, Spain
Green Submitted, gold
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