Abstract
Ubiquitin proteasome system (UPS) dysfunction has been implicated in the development of many neuronal disorders, including Parkinson's disease (PD). Previous studies focused on individual neuroprotective agents and their respective abilities to prevent neurotoxicity following a variety of toxic insults. However, the effects of the antioxidant N-acetylcysteine (NAC) on proteasome impairment-induced apoptosis have not been well characterized in human neuronal cells. The aim of this study was to determine whether cotreatment of NAC and insulin-like growth factor-1 (IGF-1) efficiently protected against proteasome inhibitor-induced cytotoxicity in SH-SY5Y cells. Our results demonstrate that the proteasome inhibitor, MG132, initiates poly(ADP-ribose) polymerase (PARP) cleavage, caspase 3 activation, and nuclear condensation and fragmentation. In addition, MG132 treatment leads to endoplasmic reticulum (ER) stress and autophagy-mediated cell death. All of these events can be attenuated without obvious reduction of MG132 induced protein ubiquitination by first treating the cells with NAC and IGF-1 separately or simultaneously prior to exposure to MG132. Moreover, our data demonstrated that the combination of the two proved to be significantly more effective for neuronal protection. Therefore, we conclude that the simultaneous use of growth/neurotrophic factors and a free radical scavenger may increase overall protection against UPS dysfunction-mediated cytotoxicity and neurodegeneration.
Highlights
In both sporadic and familial Parkinson’s disease (PD), pathways leading to neuronal death are driven mainly by two key pathological events: aberrant protein homeostasis, including aggregation of proteins that normally would be disposed by the ubiquitin-protease system (UPS) system, and mitochondrial alterations secondary to proteinopathy-associated aggregation, which result from obligate mitochondrial Ca++ loading in response to this aggregation [1, 2]
To assess the degree to which endoplasmic reticulum (ER) stress participates in MG132 induced cell death of SH-SY5Y cells, we evaluated the effect of NAC and insulin-like growth factor-1 (IGF-1) on expression of CCAAT/enhancer-binding protein homologous protein (CHOP)
The present study evaluates the neuroprotective potential of monotherapy and combination therapy of NAC and IGF-1 on proteasome dysfunction-induced neurotoxicity in human neuroblastoma SH-SY5Y cells by exploring the relationship between oxidative stress, ER stress, autophagy, and apoptotic cell death following proteasome inhibition
Summary
In both sporadic and familial Parkinson’s disease (PD), pathways leading to neuronal death are driven mainly by two key pathological events: aberrant protein homeostasis, including aggregation of proteins that normally would be disposed by the UPS system, and mitochondrial alterations secondary to proteinopathy-associated aggregation, which result from obligate mitochondrial Ca++ loading in response to this aggregation [1, 2]. During the development of PD, cellular defense mechanisms including antioxidants, the unfolded protein response (UPR), molecular chaperons, the ubiquitin-protease system (UPS), and autophagy are severely compromised [6]. Each of these defense systems offers therapeutic targets for intervention in the mechanism for their initiation and progression in the neurons
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