Abstract:

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson’s disease (PD). The mutation with the highest prevalence in LRRK2 is G2019S, while other variants in this gene have been identified as risk factors for idiopathic PD. The penetrance of LRRK2 G2019S is incomplete and possibly regulated by genetic modifiers and environmental factors. Moreover, elevated LRRK2 kinase activity has been a prime therapeutic target in LRRK2-linked and idiopathic PD. To explore the role of LRRK2 G2019S-mediated inflammatory signaling in regulating PD penetrance, we differentiated iPSC-derived microglia from a healthy individual, an isogenic control, as well as manifesting and non-manifesting LRRK2 G2019S mutation carriers. The resulting microglial models were treated with interferon gamma (IFN-γ) and subsequently with the LRRK2 kinase inhibitor MLi-2. We show that upon IFN-γ exposure, S1292 phosphorylation in LRRK2 - a readout of pathogenic kinase activity - was upregulated in a G2019S-specific manner and downregulated after MLi-2 treatment. By contrast, α-synuclein upregulation occurred exclusively in manifesting G2019S LRRK2 microglia and did not respond to MLi-2. Interestingly, RNA sequencing revealed that elevated LRRK2 kinase activity and increased a-synuclein abundance disrupt Notch signaling in a PD-specific manner in LRRK2 G2019S-mutant microglia. Together, our data further implicates LRRK2 in the propagation of inflammation in PD, suggesting a contribution of microglia to the penetrance of LRRK2 G2019S and pointing towards anti-inflammatory drugs as a potential treatment option.

Bio:

Anne Grünewald holds a PhD in Neurosciences from the University of Lübeck, Germany. As a doctoral student, she carried out research projects at the Institute of Neurogenetics in Lübeck as well as in mitochondrial laboratories at the Erasmus Medical Centre Rotterdam in the Netherlands, the University College London, UK, and the Kolling Institute at the University of Sydney in Australia. Anne Grünewald was a postdoc in the Welcome Trust Centre For Mitochondrial Research at Newcastle University, UK, funded by a fellowship from the German Research Foundation (DFG). In 2016, she joined the Luxembourg Centre for Systems Biomedicine (LCSB) at the University of Luxembourg as an ATTRACT Fellow supported by the Luxembourg Research Fund (FNR). At the LCSB, Prof. Grünewald heads the Molecular and Functional Neurobiology Group. In addition to her affiliation with the University of Luxembourg, she holds a bridge professorship with the University of Lübeck. Her research interest lies in the role of mitochondrial signaling in the pathogenesis of PD. Her team is specialized in mitochondrial function and mtDNA (single-cell) analysis techniques, which are applied to human brain tissue as well as iPSC-derived neuron and glia models. Prof. Grünewald has published >70 articles in peer-reviewed journals and has acquired >5 million EUR of grant support from international funding agencies. She is a member of the University Council and the Gender Equality Committee of the University of Luxembourg as well as a steering committee member of the University of Luxembourg Leadership Academy (ULLA). In addition, she acts as ad-hoc reviewer for multiple international foundations and journals.