LRRK2-mediated microglial activation via NFATc2: a novel mechanism of neurotoxic inflammation in synucleinopathies

Abstract

Abstract Neuroinflammation is a key pathological feature of a set of neurological disorders called synucleinopathies, which are characterized by abnormal a-synuclein (a-syn) dynamics and include Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA). Microglia, the resident macrophages of the central nervous system, are critical for orchestrating the inflammatory response in these diseases. In particular, microglia can directly bind neuron-released a-syn via receptors such as Toll-like receptor 2 (TLR2) to adopt a reactive phenotype. Here we explored the pathogenic role of Leucine-rich repeat kinase 2 (LRRK2), a PD-associated gene also known to be highly expressed in T cells, in microglial activation. We observed that neuron-released a-syn enhances LRRK2 kinase activity in microglia in a TLR2-dependent manner to induce the release of neurotoxic cytokines, TNFa and IL-6. We further determined that LRRK2 directly modulated nuclear translocation of activated T-cells cytoplasmic 2 (NFATc2) through multi-site phosphorylation. As such, modulating the LRRK2-NFATc2 cascade may be a promising therapeutic strategy for ameliorating neuroinflammation in synucleinopathies.