GSK-3β Inhibitor Alsterpaullone Attenuates MPP+-Induced Cell Damage in a c-Myc-Dependent Manner in SH-SY5Y Cells

Abstract

Mitochondrial dysfunction plays significant roles in the pathogenesis of Parkinson’s Disease (PD). The inactivation of c-Myc, a down-stream gene of Wnt/β-catenin signaling, may contribute to the mitochondria dysfunction. Inhibition of glycogen synthase kinase 3β (GSK-3β) with Alsterpaullone (Als) can activate the down-stream events of Wnt signaling. Here, we investigated the protective roles of Als against MPP+-induced cell apoptosis in SH-SY5Y cells. The data showed that Als effectively rescued c-Myc from the MPP+-induced decline via Wnt signaling. Furthermore, Als protected SH-SY5Y cells from the MPP+-induced mitochondrial fission and cell apoptosis. However, the protective roles of Als were lost under β-catenin-deficient conditions. These findings indicate that Als, a GSK-3β inhibitor, attenuated the MPP+-induced mitochondria-dependent apoptotic via up-regulation of the Wnt signaling.

Comparative proteomics study of mitochondrial electron transport system modulation in SH-SY5Y cells following MPP+ versus 6-OHDA-induced neurodegeneration

“…Based on these findings, subsequent experiments used 6-OHDA (50 µM) and MPP+ (500 µM) with a concentration associated with approximately 50% cell survival. This is similar to the treatment concentrations of 6-OHDA (Zhang et al 2014) and MPP+ (Wang et al 2018) used in previous studies. The morphology of SH-SY5Y cells treated with 50 µM 6-OHDA and 500 µM MPP+ was altered (Fig.…”

Propionic acid induces alterations in mitochondrial morphology and dynamics in SH-SY5Y cells

“…Decreased cMYC expression was previously reported in response to mitochondrial stress 42 and conversely, downregulating cMYC was shown to induce mitochondrial dysfunction by reshaping mitochondrial metabolism, network connectivity and membrane polarization 43 . Interestingly, cMYC is also implicated in the regulation of mitochondrial fission and fusion 42 , 43 and is known to increase DRP1 phosphorylation and mitochondrial localization during cell division 44 , as well as mediate mitochondrial morphological remodeling in neuronal stem cells 45 . In fact, cMYC-null fibroblasts displayed decreased mitochondrial size which is consistent with the changes induced by PPA stress 43 .…”

“…Total RNA between 0.7 and 1 μg was used to synthesize cDNA in a 20 μl reaction. Primers were selected from previously published papers 42 , 71 – 78 (Table S1 ) and their accompanying probes were designed using the Integrated DNA Technologies’ PrimerQuest Tool. All genes of interest were normalized to the nuclear gene B2M .…”

Identification of antimycin A as a c-Myc degradation accelerator via high-throughput screening

“…Treatment with other inhibitors of GSK3 such as SB415286 and lithium salts also resulted in increased levels of c-Myc in lymphoid cells ( 37 ). In SH-SY5Y cells, both alsterpaullone and LiCl could reverse the decrease of c-Myc protein induced by 1-methyl-4-phenylpyridinium ion dose-dependently, and alsterpaullone was more effective than LiCl in the protection of mitochondrial fission caused by 1-methyl-4-phenylpyridinium ion ( 38 ). In addition, another GSK3 inhibitor, SB216763, reduced ponatinib-induced cytotoxicity and degradation of c-Myc in leukemia cells ( 39 ).…”