Related Experiment Video
Updated: Dec 5, 2025
Transplantation of Human Induced Pluripotent Stem Cell-Derived Microglia in Immunocompetent Mice Brain via Non-Invasive Transnasal Route
Published on: May 31, 2022
Interferon-γ signaling synergizes with LRRK2 in neurons and microglia derived from human induced pluripotent stem
Vasiliki Panagiotakopoulou1,2, Dina Ivanyuk1,2, Silvia De Cicco1,2
1German Center for Neurodegenerative Diseases (DZNE), Tübingen, 72076, Germany.
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.
Insights
Interferon-gamma (IFN-γ) amplifies the effects of the Parkinson's-linked LRRK2 G2019S mutation, increasing neuronal vulnerability and neuroinflammation. This synergy highlights a potential mechanism linking inflammation to neurodegeneration in Parkinson's disease.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Leucine-rich repeat kinase 2 (LRRK2) mutations are linked to Parkinson's disease (PD) and immune responses.
- The interplay between LRRK2 and type II interferon (IFN-γ) in PD pathogenesis is not well understood.
Purpose of the Study:
- To investigate the synergistic effects of LRRK2 G2019S and IFN-γ on dopaminergic neurons and microglia.
- To elucidate the molecular mechanisms underlying LRRK2-IFN-γ interaction in PD.
Main Methods:
- Utilized patient-derived induced pluripotent stem cells (iPSCs) differentiated into dopaminergic neurons and microglia.
- Analyzed LRRK2 G2019S effects on AKT phosphorylation, NFAT activation, calcium signaling, and cytokine production in response to IFN-γ.
Main Results:
- IFN-γ potentiates LRRK2 G2019S-mediated inhibition of AKT phosphorylation and NFAT activation, increasing neuronal susceptibility.
- LRRK2 G2019S impairs NFAT translocation via calcium signaling and microtubule dynamics.
- Activated microglia with LRRK2 G2019S exhibit altered cytokine profiles and glycolytic metabolism, leading to neurite shortening.
Conclusions:
- Synergistic LRRK2 and IFN-γ activation represents a potential link between inflammation and neurodegeneration in Parkinson's disease.
- LRRK2-modulated neuroinflammation contributes to neuronal damage, suggesting therapeutic targets for PD.
