PAR2-mediated epigenetic upregulation of α-synuclein contributes to the pathogenesis of Parkinson׳s disease

• PAR2 signaling was increased in substantia nigra in a PD model.
• Blockade of PAR2 attenuated α-synuclein upregulation and behavioral impairment.
• Increased NF-κB activity was induced by PAR2 signaling in the PD model.
• NF-κB mediated the epigenetic upregulation of α-synuclein in the PD model.
• Inhibition of NF-κB attenuated cytokine synthesis and behavioral impairment.

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.