Abstract
Evidence suggests that crosstalk occurs between microglial leucine-rich repeat kinase 2 (LRRK2)—a regulator of neuroinflammation—and neuron-released α-synuclein (αSyn)—a promoter of microglial activation and neuroinflammatory responses—in neuroinflammation-mediated Parkinson’s disease (PD) progression. Therefore, we examined whether LRRK2 inhibition reduces the responses of microglia to neuroinflammation caused by neuron-released αSyn. We examined the neuroinflammatory responses provoked by Toll-like receptor 2 (TLR2)-positive αSyn of neuronal cells using an LRRK2 inhibitor in the mouse glioma cells, rat primary microglia, and human microglia cell line; and the effects of LRRK2 inhibitor in the co-culture of ectopic αSyn-expressing human neuroblastoma cells and human microglia cells and in mouse models by injecting αSyn. We analyzed the association between LRRK2 activity and αSyn oligomer and TLR2 levels in the substantia nigra tissues of human patients with idiopathic PD (iPD). The TLR2-specific αSyn elevated LRRK2 activity and neuroinflammation, and the LRRK2 inhibitor ameliorated neuroinflammatory responses in various microglia cells, alleviated neuronal degeneration along with neuroinflammation in the co-culture, and blocked the further progression of locomotor failure and dopaminergic neuronal degeneration caused by TLR2-specific αSyn in mice. Furthermore, LRRK2 phosphorylation was increased in patients with iPD showing αSyn-specific high TLR2 level. These results suggest the application of LRRK2 inhibitors as a novel therapeutic approach against αSyn-mediated PD progression.
Highlights
Neuroinflammatory responses play a crucial role in the defense mechanisms of the brain [1]
The stimulator of neuroinflammation in patients with Parkinson’s disease (PD) remains elusive, but previous studies have demonstrated that the release of α-synuclein from neurons is responsible for the activation of microglia via the Toll-like receptors (TLRs), CD36, or P2X7 receptor [6–8]
Upregulation of Leucine-rich repeat kinase 2 (LRRK2) Activity Is Promoted by Toll-like receptor 2 (TLR2) Activation via the αSyn Oligomer
Summary
Neuroinflammatory responses play a crucial role in the defense mechanisms of the brain [1]. Neuroinflammation may act as a double-edged blade because the release of excessive quantities of pro-inflammatory cytokines worsens the degeneration of neurons in patients with neurodegenerative diseases, which accelerates the disease progression [2]. The number of reactive microglia is higher in the brains of patients with Parkinson’s disease (PD) [3], and pro-inflammatory cytokine levels are higher in the biofluids, such as the cerebrospinal fluid and plasma, of the former than those of the latter [4,5]. The stimulator of neuroinflammation in patients with PD remains elusive, but previous studies have demonstrated that the release of α-synuclein (αSyn) from neurons is responsible for the activation of microglia via the Toll-like receptors (TLRs), CD36, or P2X7 receptor [6–8]. Leucine-rich repeat kinase 2 (LRRK2) is considered a modulator of neuroinflammation because its kinase activity regulates microglial reactivity and the levels of pro-inflammatory cytokines [10,11]. Our previous study showed that the upregulated kinase activity of G2019S LRRK2 mutants promoted microglia-derived neuroinflammation [13]
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