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.
journal_name
Nat Communjournal_title
Nature communicationsauthors
Panagiotakopoulou V,Ivanyuk D,De Cicco S,Haq W,Arsić A,Yu C,Messelodi D,Oldrati M,Schöndorf DC,Perez MJ,Cassatella RP,Jakobi M,Schneiderhan-Marra N,Gasser T,Nikić-Spiegel I,Deleidi Mdoi
10.1038/s41467-020-18755-4subject
Has Abstractpub_date
2020-10-14 00:00:00pages
5163issue
1issn
2041-1723pii
10.1038/s41467-020-18755-4journal_volume
11pub_type
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