PAR2-mediated epigenetic upregulation of α-synuclein contributes to the pathogenesis of Parkinson׳s disease.
Brain Res
; 1565: 82-9, 2014 May 27.
Article
in En
| MEDLINE
| ID: mdl-24747612
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-1ß 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Substantia Nigra
/
NF-kappa B
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MPTP Poisoning
/
Receptor, PAR-2
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Epigenesis, Genetic
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Alpha-Synuclein
Type of study:
Etiology_studies
/
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Brain Res
Year:
2014
Document type:
Article
Affiliation country: