Abstract
BackgroundReactive astrogliosis is a remarkable pathogenetic hallmark of the brains of Parkinson’s disease (PD) patients, but its progressive fate and regulation mechanisms are poorly understood. In this study, growth arrest specific 1 (Gas1), a tumor growth suppressor oncogene, was identified as a novel modulator of the cell apoptosis of reactive astrocytes in primary culture and the injured substantia nigra.MethodsAnimal models and cell cultures were utilized in the present study. Lipopolysaccharide (LPS)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated animal models were used to detect Gas1 expression in the brain via immunohistochemistry and western blot. Cell cultures were performed to analyze Gas1 functions in the viability and apoptosis of reactive astrocytes and SH-SY5Y cells by double labeling, CCK-8, LDH, TUNEL, flow cytometry, and siRNA knockdown methods.ResultsGas1 expressions were significantly elevated in the majority of the reactive astrocytes of the brains with LPS or MPTP insults. In the injured substantia nigras, GFAP-positive astrocytes exhibited higher levels of cleaved caspase-3. In cell culture, the up-regulated Gas1 expression induced apoptosis of reactive astrocytes that were insulted by LPS in combination with interferon-γ and tumor necrosis factor-a. This effect was confirmed through siRNA knockdown of Gas1 gene expression. Finally and interestingly, the potential underlying signaling pathways were evidently related to an increase in the Bax/Bcl-2 ratio, the abundant generation of reactive oxygen species and the activation of cleaved caspase-3.ConclusionsThis study demonstrated that the up-regulation of inducible Gas1 contributed to the apoptosis of reactive astrocytes in the injured nigra. Gas1 signaling may function as a novel regulator of astrogliosis and is thus a potential intervention target for inflammatory events in PD conditions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0643-2) contains supplementary material, which is available to authorized users.
Highlights
Reactive astrogliosis is a remarkable pathogenetic hallmark of the brains of Parkinson’s disease (PD) patients, but its progressive fate and regulation mechanisms are poorly understood
The results revealed that the apoptotic proportions of astrocytes in both the early and later stages of apoptosis were increased in the groups exposed to LPS, interferon γ (IFNγ), and tumor necrosis factor α (TNFα) treatment compared with the control (Fig. 5e, f )
The results revealed that the siGas1-3 effectively down-regulated growth arrest specific 1 (Gas1) expression in the astrocytes compared with the scrambled siRNA control (Fig. 6a). siGas1-3 was selected for the biological effect analysis of Gas1 knockdown
Summary
Reactive astrogliosis is a remarkable pathogenetic hallmark of the brains of Parkinson’s disease (PD) patients, but its progressive fate and regulation mechanisms are poorly understood. Many studies have demonstrated that neuroinflammation mediated by astrocytes and microglial cells may play a vital role in the death or survival of nigral dopaminergic neurons [1]. Cell apoptosis among the activated astrocytes has been noted in vivo in the brains of Alzheimer’s disease [7] and HIV encephalitis [8] patients. There is a growing consensus that the apoptosis of activated astrocytes may present as a self-regulatory mechanism to control the severity of inflammation in the brain [11]. The molecular mechanisms underlying this self-regulation of the apoptosis of astrocytes are still far from clear
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