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.
Highlights
Parkinson’s disease-associated kinase leucine-rich repeat kinase 2 (LRRK2) has been linked to IFN type II (IFN-γ) response in infections and to dopaminergic neuronal loss
To examine the impact of IFN-γ signaling on human neurons, we employed induced pluripotent stem cell-derived neural precursor cells (NPCs)
To evaluate whether Parkinson’s disease (PD)-associated LRRK2 missense mutations influence the IFN-γ-driven induction of LRRK2 expression, we used NPC lines derived from patients carrying the LRRK2 G2019S mutation and compared them to corresponding isogenic controls[24,25]
Summary
Parkinson’s disease-associated kinase LRRK2 has been linked to IFN type II (IFN-γ) response in infections and to dopaminergic neuronal loss. Emerging data suggest that immune dysregulation contributes to the progression, and the onset of neurodegenerative diseases such as Parkinson’s disease (PD)[1] In this respect, human genetics and functional genomics studies indicate that interferon (IFN)-mediated signaling pathways, including those of IFN type I and type II, play a role in brain aging and human neurodegenerative diseases[2,3]. Kozina et al showed that pathogenic mutations in the human leucine-rich repeat kinase 2 (LRRK2) gene, the most common genetic cause of familial PD14, synergizes with lipopolysaccharide (LPS)-induced inflammation to potentiate DA neurodegeneration through IFN-γ-mediated immune responses[13]. We show that G2019S mutation sensitizes neurons to IFN-γ signaling and we provide evidence that LRRK2 regulates microglial response to IFN-γ by modulating immune metabolic reprogramming These findings have potential therapeutic implications as compounds targeting LRRK2 are currently being tested in clinical trials for PD
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