Therapeutic effect of a histone demethylase inhibitor in Parkinson's disease.
Cell Death Dis
; 11(10): 927, 2020 10 28.
Article
em En
| MEDLINE
| ID: mdl-33116116
ABSTRACT
Iron accumulation in the substantia nigra is recognized as a hallmark of Parkinson's disease (PD). Therefore, reducing accumulated iron and associated oxidative stress is considered a promising therapeutic strategy for PD. However, current iron chelators have poor membrane permeability and lack cell-type specificity. Here we identified GSK-J4, a histone demethylase inhibitor with the ability to cross blood brain barrier, as a potent iron suppressor. Only a trace amount of GSK-J4 significantly and selectively reduced intracellular labile iron in dopaminergic neurons, and suppressed H2O2 and 6-OHDA-induced cell death in vitro. The iron-suppressive effect was mainly mediated by inducing an increase in the expression of the iron exporter ferroportin-1. In parallel, GSK-J4 rescued dopaminergic neuron loss and motor defects in 6-OHDA-induced PD rats, which was accompanied by reduction of oxidative stress. Importantly, GSK-J4 rescued the abnormal changes of histone methylation, H3K4me3 and H3K27me3 during 6-OHDA treatment although the iron-suppressive and neuroprotective effects were sensitive to H3K4me3 inhibition only. Also, upregulating H3K4me3 increased ferroportin-1 expression and neuroprotection. Taken together, we demonstrate a previously unappreciated action of GSK-J4 on cell-specific iron suppression and neuroprotection via epigenetic mechanism. Compared with conventional iron chelators, this compound has a stronger therapeutic potential for PD.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
/
Quelantes de Ferro
/
Histona Desmetilases
Limite:
Animals
/
Humans
Idioma:
En
Ano de publicação:
2020
Tipo de documento:
Article