Autophagy Activation Is Involved in Acidic Fibroblast Growth Factor Ameliorating Parkinson's Disease via Regulating Tribbles Homologue 3.

Xingfeng Zhong,Beini Wang,Jun Xiong,Peipei Zheng,Jian Xiao,Yaqian Liu,Xiaoli Hu,Guanyinsheng Zhang,Yanqing Wu,Junming Ye,Ke Xu,Yuan Yuan

doi:10.3389/fphar.2019.01428

Abstract

Parkinson’s disease (PD) is a degenerative disorder of the central nervous system, resulting in loss of dopamine neurons. Excessive endoplasmic reticulum (ER) stress and autophagy dysfunction play a crucial role on Parkinson’s disease (PD) development. It has been showed that acidic fibroblast growth factor (aFGF) alleviates the development of PD by inhibiting ER stress. But the role of autophagy and its relationship with ER stress during aFGF treatment for PD has not been elucidated. We found that both aFGF and rapamycin (Rapa) improved 6-Hydroxy Dopamine (6-OHDA)-induced PD development as shown with histomorphology results in striatum and substantia nigra (SNpc). Additionally, aFGF promoted autophagy with increasing mTOR and decreasing p62 expressions, and then exerts its neuroprotective role in 6-OHDA-treated PC12 cells, which were abolished by chloroquine (CQ) treatment. Moreover, 4-phenylbutyric acid (4-PBA) administration inhibited the expressions of autophagy markers during 6-OHDA-treated PC12 cells, which was similar with aFGF treating PC12 cells under 6-OHDA condition. Furthermore, we had detected the expressions of CHOP and its downstream factor, tribbles homologue 3 (TRB3), a pro-apoptotic protein. We found that TRB3 and CHOP expressions were significantly downregulated after treating with aFGF and 4-PBA in 6-OHDA-treated PC12 cells and PD model. Taken together, this study has demonstrated that aFGF treatment ameliorates 6-OHDA-induced elevated ER stress and subsequently suppression of autophagy via inhibiting TRB3 activation, and consequently ameliorates 6-OHDA-induced neurotoxicity.

Highlights

Parkinson's disease (PD) is a kind of neurodegenerative disease, which is associated with the abnormally accumulated α-synuclein (α-syn) in the substantia nigra pars compacta (SNpc)
Compared with that in 6-OHDA group, acidic fibroblast growth factor (aFGF) treatment significantly decreased the number of turns of 6-OHDA mice, indicating aFGF effectively alleviates the rotational behavior of PD rats
It was found that the rats in 6-OHDA group and CQ group have showed damaged striatum, irregular hyperplasia and scar, decreased Nissl bodies, which were reversed by aFGF or Rapa treatment

Summary

Introduction

Parkinson's disease (PD) is a kind of neurodegenerative disease, which is associated with the abnormally accumulated α-synuclein (α-syn) in the substantia nigra pars compacta (SNpc). In the early study of PD development, gene mutation of α-syn on the autosome caused excessive aggregation damage (Fujiwara et al, 2002; Hasegawa et al, 2002; Samuel et al, 2016; Longo et al, 2017). The cellular mechanisms, include autophagy (Magalhaes et al, 2016), endoplasmic reticulum. Regulation of cellular stress may be the target for treating PD. The previous studies have showed that aFGF can attenuate 6-OHDA-induced dopaminergic neuron toxicity (Wei et al, 2014). The mechanism underlying aFGF treating for PD is through inhibiting ER stress (Wei et al, 2014). Promotion of autophagy is the mechanism during aFGF treating for spinal cord injury (Li et al, 2018). There is no studies to reveal on role of autophagy, and its' relationship with ER stress during aFGF treating for PD

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