Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia
| Autor: | Aleksandra Arsić, David C. Schöndorf, Cong Yu, Ivana Nikić-Spiegel, Nicole Schneiderhan-Marra, Vasiliki Panagiotakopoulou, Michela Deleidi, Maria-Jose Perez, Silvia De Cicco, Meike Jakobi, Dina Ivanyuk, Wadood Haq, Thomas Gasser, Ruggiero Pio Cassatella |
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| Rok vydání: | 2020 |
| Předmět: |
0303 health sciences
Cell type Microglia Kinase Chemistry Neurodegeneration NFAT Inflammation medicine.disease LRRK2 nervous system diseases 3. Good health Cell biology 03 medical and health sciences 0302 clinical medicine medicine.anatomical_structure medicine medicine.symptom Induced pluripotent stem cell 030217 neurology & neurosurgery 030304 developmental biology |
| DOI: | 10.1101/2020.01.30.925222 |
| Popis: | Increasing evidence suggests a role for interferons (IFNs) in neurodegeneration. Parkinson’s disease (PD) associated kinase LRRK2 has been implicated in IFN type II (IFN) response in infections and nigral neuronal loss. However, whether and how LRRK2 synergizes with IFN-γ still remains unclear. Here, we employed dopaminergic (DA) neurons and microglia differentiated from patient induced pluripotent stem cells to unravel the role of IFN-γ in LRRK2-PD. We show that IFN-γ induces LRRK2 expression in both DA neurons and microglial cells. LRRK2-G2019S, the most common PD-associated mutation, sensitizes DA neurons to IFN-γ by decreasing AKT phosphorylation. IFN-γ suppresses NFAT activity in both neurons and microglia and synergistically enhances LRRK2-induced defects of NFAT activation. Furthermore, LRRK2-G2019S negatively regulates NFAT via calcium and microtubule dynamics. Importantly, we uncover functional consequences of the reduction of NFAT activity in both cell types, namely defects of neurite elongation and alteration of microglial activation profile and motility. We propose that synergistic IFN-γ/LRRK2 activation serves as a direct link between inflammation and neurodegeneration in PD. |
| Databáze: | OpenAIRE |
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