Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem cells

Vasiliki Panagiotakopoulou, Dina Ivanyuk, Silvia De Cicco, Wadood Haq, Aleksandra Arsić, Cong Yu, Daria Messelodi, Marvin Oldrati, David C. Schöndorf, Maria-Jose Perez, Ruggiero Pio Cassatella, Meike Jakobi, Nicole Schneiderhan-Marra, Thomas Gasser, Ivana Nikić-Spiegel and Michela Deleidi ()
Additional contact information
Vasiliki Panagiotakopoulou: German Center for Neurodegenerative Diseases (DZNE)
Dina Ivanyuk: German Center for Neurodegenerative Diseases (DZNE)
Silvia De Cicco: German Center for Neurodegenerative Diseases (DZNE)
Wadood Haq: University of Tübingen
Aleksandra Arsić: University of Tübingen
Cong Yu: German Center for Neurodegenerative Diseases (DZNE)
Daria Messelodi: German Center for Neurodegenerative Diseases (DZNE)
Marvin Oldrati: German Center for Neurodegenerative Diseases (DZNE)
David C. Schöndorf: German Center for Neurodegenerative Diseases (DZNE)
Maria-Jose Perez: German Center for Neurodegenerative Diseases (DZNE)
Ruggiero Pio Cassatella: German Center for Neurodegenerative Diseases (DZNE)
Meike Jakobi: NMI Natural and Medical Sciences Institute at the University of Tübingen
Nicole Schneiderhan-Marra: NMI Natural and Medical Sciences Institute at the University of Tübingen
Thomas Gasser: German Center for Neurodegenerative Diseases (DZNE)
Ivana Nikić-Spiegel: University of Tübingen
Michela Deleidi: German Center for Neurodegenerative Diseases (DZNE)

Nature Communications, 2020, vol. 11, issue 1, 1-17

Abstract: Abstract Parkinson’s disease-associated kinase LRRK2 has been linked to IFN type II (IFN-γ) response in infections and to dopaminergic neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ remains unclear. In this study, we employed dopaminergic neurons and microglia differentiated from patient-derived induced pluripotent stem cells carrying LRRK2 G2019S, the most common Parkinson’s disease-associated mutation. We show that IFN-γ enhances the LRRK2 G2019S-dependent negative regulation of AKT phosphorylation and NFAT activation, thereby increasing neuronal vulnerability to immune challenge. Mechanistically, LRRK2 G2019S suppresses NFAT translocation via calcium signaling and possibly through microtubule reorganization. In microglia, LRRK2 modulates cytokine production and the glycolytic switch in response to IFN-γ in an NFAT-independent manner. Activated LRRK2 G2019S microglia cause neurite shortening, indicating that LRRK2-driven immunological changes can be neurotoxic. We propose that synergistic LRRK2/IFN-γ activation serves as a potential link between inflammation and neurodegeneration in Parkinson’s disease.

Date: 2020
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DOI: 10.1038/s41467-020-18755-4

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