Da-Bu-Yin-Wan Improves the Ameliorative Effect of DJ-1 on Mitochondrial Dysfunction Through Augmenting the Akt Phosphorylation in a Cellular Model of Parkinson's Disease.

Yi Zhang,Lin Li,Nai-Hong Chen,Zhen-Yu Guo,Ping Li,Hong-Mei Sun,Zhen-Zhen Wang,Jing-Hong Hu,Yuan-Yuan Wang,Xiao-Gang Gong,Wan-Di Feng

doi:10.3389/fphar.2018.01206

Abstract

Da-Bu-Yin-Wan (DBYW) is recorded originally in China over six centuries ago, and it is used to treat Parkinson’s disease (PD) clinically in recent decades. DJ-1 is a homodimeric protein linked to early-onset PD, and found in the mitochondria. In addition, DJ-1 could protect the cells by regulating gene transcription and modulating the Akt signal pathways. Therefore, in this research, we aimed to investigate the ameliorative effect of DBYW on mitochondria in the view of the DJ-1 and Akt signaling. Rat adrenal pheochromocytoma cell line PC-12 was transfected with the plasmid pcDNA3-Flag-DJ-1 (pDJ-1). Subsequently, PC-12 cells were exposed to the PD-related mitochondrial toxin (1-methyl-4-phenylpyridinium) without/with the DBYW. After transfected with the plasmid pDJ-1, the 1-methyl-4-phenylpyridinium-induced toxicity was decreased, and the DJ-1 expression in protein level was increased. DJ-1 overexpression not only increased the mitochondrial mass, but also improved the total ATP content. Moreover, Akt phosphorylation was augmented by DJ-1 overexpression. Additionally, DBYW enhanced the above effects. Conclusively, these findings indicate that DBYW promotes the ameliorative effects of DJ-1 on mitochondrial dysfunction at least through augmenting the Akt phosphorylation in 1-methyl-4-phenylpyridinium-treated PC-12 cells.

Highlights

Parkinson’s disease (PD) is a highly debilitating neurodegenerative disorder that induces body rigidity, tremor, bradykinesia, and postural instability (Kalia and Lang, 2015)
We found a significant loss of PC-12 cells treated with 1 mM MPP+ for 48 h
PC-12 cells have been widely served as a cellular model system for investigating PD (Hatanaka, 1981; Westerink and Ewing, 2008), because they have the enzymes for dopamine synthesis, metabolism and transportation (Hatanaka, 1981; Tuler et al, 1989)

Summary

Introduction

Parkinson’s disease (PD) is a highly debilitating neurodegenerative disorder that induces body rigidity, tremor, bradykinesia, and postural instability (Kalia and Lang, 2015). The PD pathology is characterized by gradual loss of dopaminergic neurons in the substantia nigra (Pagonabarraga et al, 2015), the underlying mechanisms still need to be clarified even though the disease was first described 200 years ago (Przedborski, 2017). Given the critical role of mitochondria in cellular function, it is convincing that mitochondrial dysfunction has appeared as an important mechanism at the coincidence of genetic, environmental and neurotoxin threatens to PD (Dagda et al, 2009). Akt exerts its neuroprotective effect on neuronal cells by phosphorylation (Franke et al, 2003), whereas Akt signaling defection has partly linked to the pathological process of PD (Burke, 2007; Levy et al, 2009). DJ-1 is important for Akt phosphorylation enhancement on oxidative stress in the models of PD (Aleyasin et al, 2010)

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