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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.

SUBMITTER: Panagiotakopoulou V

PROVIDER: S-EPMC7560616 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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

Panagiotakopoulou Vasiliki V Ivanyuk Dina D De Cicco Silvia S Haq Wadood W Arsić Aleksandra A Yu Cong C Messelodi Daria D Oldrati Marvin M Schöndorf David C DC Perez Maria-Jose MJ Cassatella Ruggiero Pio RP Jakobi Meike M Schneiderhan-Marra Nicole N Gasser Thomas T Nikić-Spiegel Ivana I Deleidi Michela M

Nature communications 20201014 1

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 AK ...[more]

PMID: 33057020

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Project description:ImportanceAlthough considerable effort has been expended developing drug candidates for Alzheimer disease, none have yet succeeded owing to the lack of efficacy or to safety concerns. One potential shortcoming of current approaches to Alzheimer disease drug discovery and development is that they rely primarily on transformed cell lines and animal models that substantially overexpress wild-type or mutant proteins. It is possible that drug development failures thus far are caused in part by the limits of these approaches, which do not accurately reveal how drug candidates will behave in naive human neuronal cells.ObjectiveTo analyze purified neurons derived from human induced pluripotent stem cells from patients carrying 3 different presenilin 1 (PS1) mutations and nondemented control individuals in the absence of any overexpression. We tested the efficacy of γ-secretase inhibitor and γ-secretase modulator (GSM) in neurons derived from both normal control and 3 PS1 mutations (A246E, H163R, and M146L).Design, setting, and participantsAdult human skin biopsies were obtained from volunteers at the Alzheimer Disease Research Center, University of California, San Diego. Cell cultures were treated with γ-secretase inhibitor or GSM. Comparisons of total β-amyloid (Aβ) and Aβ peptides 38, 40, and 42 in the media were made between vehicle- vs drug-treated cultures.Main outcomes and measuresSoluble Aβ levels in the media were measured by enzyme-linked immunosorbent assay.ResultsAs predicted, mutant PS1 neurons exhibited an elevated Aβ42:Aβ40 ratio (P < .05) at the basal state as compared with the nondemented control neurons. Treatment with a potent non-nonsteroidal anti-inflammatory druglike GSM revealed a new biomarker signature that differs from all previous cell types and animals tested. This new signature was the same in both the mutant and control neurons and consisted of a reduction in Aβ42, Aβ40, and Aβ38 and in the Aβ42:Aβ40 ratio, with no change in the total Aβ levels.Conclusions and relevanceThis biomarker discrepancy is likely due to overexpression of amyloid precursor protein in the transformed cellular models. Our results suggest that biomarker signatures obtained with such models are misleading and that human neurons derived from human induced pluripotent stem cells provide a unique signature that will more accurately reflect drug response in human patients and in cerebrospinal fluid biomarker changes observed during GSM treatment.

Dataset Information

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

Publications

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

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