Salidroside Promotes the Pathological α-Synuclein Clearance Through Ubiquitin-Proteasome System in SH-SY5Y Cells

Tao Li,Ruixin Yang,Qian Yang,Jianzong Chen,Ruru Li,Yang Feng,Lu Huang,Leitao Wu

doi:10.3389/fphar.2018.00377

Tao Li, Ruixin Yang + Show 6 more

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https://doi.org/10.3389/fphar.2018.00377

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Abstract

Parkinson’s disease (PD) is characterized by the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) in the surviving SNc neurons. LBs formation is caused by the accumulation of α-synuclein (α-syn) or phosphorylated α-syn at serine-129 (pSer129-α-syn), which is implicated in the pathological progression of PD. Salidroside (Sal), the main active ingredient of the root of Rhodiola rosea L., has been reported to have potent neuroprotective properties in our previous investigations. Here, we investigated the effects of Sal on 6-OHDA and overexpresssion of WT/A30P-α-syn-induced pathological α-syn increase and the mechanism behind it in SH-SY5Y cells. We found Sal displays neuroprotective effects against 6-hydroxydopamine (6-OHDA)-induced cytotoxicity. Sal decreased the pSer129-α-syn level mainly by maintaining the normal function of ubiquitin-proteasome system (UPS). Furthermore, Sal promoted the clearance of α-syn and protected the cell viability mainly through recovered the 20S proteasome activity in WT/A30P-α-syn-transfected cells. These data provide new mechanistic insights into the neuroprotective effects of Sal and Sal may be a promising therapy to slow neurodegeneration in PD.Highlights: Sal protects cells and decreases the pSer129-α-syn protein level in 6-OHDA-induced impairmental and dysfunctional SH-SY5Y cells.Sal promotes the clearance of α-syn and protects the cell viability mainly through recovering the 20S proteasome activity in WT/A30P-α-syn plasmids transfected cells.Maintaining the normal function of the UPS may be one of the important mechanisms of Sal in neuroprotective effects.

Highlights

Parkinson’s disease (PD) is the second most common neurodegenerative disorder
We investigated the potential effects of Salidroside [p-hydroxyphenethyl-β-D-glucoside (Sal) on the pathological increase in α-syn induced by 6-OHDA and WT/A30P-α-syn transfection in SH-SY5Y cells and the mechanisms underlying this biology
Sal maintained the normal function of the UPS by recovering the protein levels of ubiquitin C-terminal hydrolase L1 (UCH-L1), PARKIN, free ubiquitin, and 20S proteasome activity

Summary

Introduction

Parkinson’s disease (PD) is the second most common neurodegenerative disorder. The pathological hallmarks of PD are the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNc) and the presence of Lewy bodies (LBs) in the surviving SNc neurons. Studies suggested that approximately 90% of the α-syn deposited in LBs is phosphorylated at Ser-129 (pSer129-α-syn) (Fujiwara et al, 2002; Anderson et al, 2006). Postmortem studies of human α-synucleinopathies and animal PD models have shown that the level of pSer129-α-syn is linked to the disease progression (Braithwaite et al, 2012; Sato et al, 2013). Investigations of A53T/A30P transgenic mouse models have shown that the accumulation of A53T/A30P-α-syn resulted in the loss of SNc neurons, dysfunction of DA neurons, and behavioral impairments (Freichel et al, 2007; Paumier et al, 2013). The accumulation of pathological α-syn is likely involved in the neuronal degeneration observed in PD and it may be a potential target for therapeutic intervention

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