Research ArticleNEURODEGENERATIVE DISEASES

LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies

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Science Translational Medicine  14 Oct 2020:
Vol. 12, Issue 565, eaay0399
DOI: 10.1126/scitranslmed.aay0399

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Understanding microglia response to α-synuclein

α-Synuclein (α-syn) deposition is a major hallmark of several neurodegenerative diseases. α-Syn can induce microglia activation and subsequent neurodegeneration; however, the mechanisms mediating microglia response to α-syn are not completely elucidated. Now, Kim et al. show that neuron-released α-syn promotes activation of leucine-rich repeat kinase 2 (LRRK2) in rodent microglia via TLR2 that in turn triggered a proinflammatory cascade through activation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). Inhibiting LRRK2 ameliorated neuropathology in a mouse model of synucleinopathy.

Abstract

Synucleinopathies are neurodegenerative disorders characterized by abnormal α-synuclein deposition that include Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy. The pathology of these conditions also includes neuronal loss and neuroinflammation. Neuron-released α-synuclein has been shown to induce neurotoxic, proinflammatory microglial responses through Toll-like receptor 2, but the molecular mechanisms involved are poorly understood. Here, we show that leucine-rich repeat kinase 2 (LRRK2) plays a critical role in the activation of microglia by extracellular α-synuclein. Exposure to α-synuclein was found to enhance LRRK2 phosphorylation and activity in mouse primary microglia. Furthermore, genetic and pharmacological inhibition of LRRK2 markedly diminished α-synuclein–mediated microglial neurotoxicity via lowering of tumor necrosis factor–α and interleukin-6 expression in mouse cultures. We determined that LRRK2 promoted a neuroinflammatory cascade by selectively phosphorylating and inducing nuclear translocation of the immune transcription factor nuclear factor of activated T cells, cytoplasmic 2 (NFATc2). NFATc2 activation was seen in patients with synucleinopathies and in a mouse model of synucleinopathy, where administration of an LRRK2 pharmacological inhibitor restored motor behavioral deficits. Our results suggest that modulation of LRRK2 and its downstream signaling mediator NFATc2 might be therapeutic targets for treating synucleinopathies.

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