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

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.

• Authors: 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, Michela Deleidi
• Journal: Nature communications (Nat Commun) Vol. 11 Issue 1 Pg. 5163 (10 14 2020) ISSN: 2041-1723 [Electronic] England
• PMID: 33057020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• IFNG protein, human
• NFATC Transcription Factors
• NFATC2 protein, human
• Interferon-gamma
• LRRK2 protein, human
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Topics

• Calcium Signaling (genetics)
• Cell Differentiation
• Cytokines (metabolism)
• Dopaminergic Neurons (immunology, metabolism)
• Gene Knockout Techniques
• Glycolysis (genetics)
• HEK293 Cells
• Humans
• Induced Pluripotent Stem Cells (physiology)
• Interferon-gamma (immunology, metabolism)
• Intravital Microscopy
• Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (genetics, metabolism)
• Microglia (immunology, metabolism)
• Microtubules (metabolism)
• Mutation
• NFATC Transcription Factors (metabolism)
• Parkinson Disease (genetics, immunology, pathology)
• Primary Cell Culture
• Signal Transduction (genetics, immunology)
• THP-1 Cells