Interferon-γ signaling synergizes with LRRK2 in human neurons and microglia
De Cicco, S.; Ivanyuk, D.; Haq, W.; Panagiotakopoulou, V.; Arsic, A.; Schoendorf, D.; Yu, C.; Perez, M.-J.; Cassatella, R. P.; Jakobi, M.; Schneiderhan-Marra, N.; Nikic-Spiegel, I.; Gasser, T.; Deleidi, M.
Show abstract
Increasing evidence suggests a role for interferons (IFNs) in neurodegeneration. Parkinsons 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-{gamma} still remains unclear. Here, we employed dopaminergic (DA) neurons and microglia differentiated from patient induced pluripotent stem cells to unravel the role of IFN-{gamma} in LRRK2-PD. We show that IFN-{gamma} induces LRRK2 expression in both DA neurons and microglial cells. LRRK2-G2019S, the most common PD-associated mutation, sensitizes DA neurons to IFN-{gamma} by decreasing AKT phosphorylation. IFN-{gamma} 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-{gamma}/LRRK2 activation serves as a direct link between inflammation and neurodegeneration in PD.
Matching journals
The top 10 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Expression of ALS-PFN1 impairs vesicular degradation in iPSC-derived microglia 97%
- SKA2 regulated hyperactive secretory autophagy drives neuroinflammation-induced neurodegeneration 96%
- Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases 96%
Similar papers in this journal
Similar papers in this journal
- Cell-autonomous immune dysfunction driven by disrupted autophagy in C9orf72-ALS iPSC-derived microglia contributes to neurodegeneration 96%
- VMAT2 dysfunction impairs vesicular dopamine uptake, driving its oxidation and α-synuclein pathology in DJ-1-linked Parkinson's disease neurons 95%
- Mitochondrial pyruvate metabolism regulates the activation of quiescent adult neural stem cells 95%
Similar papers in this journal
- Metabolic reprogramming and altered ATP content impair neuroprotective functions of microglia in β-glucocerebrosidase deficiency models 96%
- IRF3 regulates neuroinflammatory responses and the expression of genes associated with Alzheimer's disease. 95%
- Helicobacter pylori infection and α-synuclein pathology drive parallel neurodegenerative pathways in the substantia nigra 95%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.