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Article

LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss

1
InAm Neuroscience Research Center, Wonkwang University, Sanbon-ro 321, Gunpo-si 15865, Gyeonggi-do, Korea
2
Paik Institute for Clinical Research, Inje University College of Medicine, Busan-si 47392, Korea
3
Department of Convergence Biomedical Science, Inje University College of Medicine, Busan-si 47392, Korea
4
Department of Neurology, Sanbon Medical Center, College of Medicine, Wonkwang University, Sanbon-ro 321, Gunpo-si 15865, Gyeonggi-do, Korea
*
Authors to whom correspondence should be addressed.
Academic Editors: Hans Zempel, Natja Haag and Juliane Bremer
Cells 2022, 11(5), 861; https://doi.org/10.3390/cells11050861
Received: 13 January 2022 / Revised: 4 February 2022 / Accepted: 8 February 2022 / Published: 2 March 2022
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. View Full-Text
Keywords: Parkinson’s disease; α-synuclein; leucine-rich repeat kinase 2 (LRRK2); neuroinflammation Parkinson’s disease; α-synuclein; leucine-rich repeat kinase 2 (LRRK2); neuroinflammation
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MDPI and ACS Style

Ho, D.-H.; Nam, D.; Seo, M.; Park, S.-W.; Seol, W.; Son, I. LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss. Cells 2022, 11, 861. https://doi.org/10.3390/cells11050861

AMA Style

Ho D-H, Nam D, Seo M, Park S-W, Seol W, Son I. LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss. Cells. 2022; 11(5):861. https://doi.org/10.3390/cells11050861

Chicago/Turabian Style

Ho, Dong-Hwan, Daleum Nam, Mikyoung Seo, Sung-Woo Park, Wongi Seol, and Ilhong Son. 2022. "LRRK2 Inhibition Mitigates the Neuroinflammation Caused by TLR2-Specific α-Synuclein and Alleviates Neuroinflammation-Derived Dopaminergic Neuronal Loss" Cells 11, no. 5: 861. https://doi.org/10.3390/cells11050861

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