title: PAR2-mediated epigenetic upregulation of α-synuclein contributes to the pathogenesis of Parkinson׳s disease.
abstract: Parkinson׳s disease (PD) is a common neurodegenerative disorder characterized by the selective degeneration of projecting dopaminergic neurons in the substantia nigra and diminished dopamine levels in the striatum. Accumulating evidences demonstrate that the aggregation of extracellular α-synuclein contributes to the neuroinflammation and neuronal injury in the substantia nigra in the brain of patients with PD. Proteinase-activated receptor 2 (PAR2), a G-protein coupled receptor, is expressed throughout the peripheral and central nerve system. The present study aims to investigate the involvement of PAR2-NF-κB signaling in the upregulation of α-synuclein and motor dysfunction in the rodent model of PD. Significantly increased expression of α-synuclein was observed in the substantia nigra of the rats injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In these rats, significantly increased nigral PAR2 was observed, and blockade of PAR2 signaling reduced the α-synuclein synthesis in substantia nigra and recovered the motor dysfunction in the rats injected with MPTP. Furthermore, significantly increased phosphorylation of NF-κB subunit p65 was detected in these rats, which was abolished by the inhibition of PAR2 signaling. Blockade of NF-κB signaling significantly decreased histone H3 acetylation in Snca promoter region and α-synuclein expression in substantia nigra. It also decreased the synthesis of cytokine IL-1β and TNF-α in substantia nigra and recovered the motor dysfunction in the rats injected with MPTP. These results indicated the critical involvement of PAR2-NF-κB signaling in the upregulation of α-synuclein and motor dysfunction in the rodent model of PD, and shed light on the development of novel approaches for the treatment of patients with PD.
authors.affiliation: Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.affiliation: Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.affiliation: Department of Pain Management, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Xu-Li
authors.initials: XL
authors.lastname: Zhao
authors.affiliation: Department of Orthopedic, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China.
authors.forename: Xue-Mei
authors.initials: XM
authors.lastname: Zhao
authors.affiliation: Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, China. Electronic address: zhangjiansd01@163.com.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D020267:MPTP Poisoning / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D044464:Receptor, PAR-2 / Q000378:metabolism*; D013378:Substantia Nigra / Q000378:metabolism*; D015854:Up-Regulation; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D016328:NF-kappa B; D044464:Receptor, PAR-2; D051844:alpha-Synuclein
keywords: Histone acetylation; Nuclear factor-κB; Parkinson׳s disease; Proteinase-activated receptor 2; α-synuclein