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

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 alpha-synuclein (alpha-syn) or phosphorylated alpha-syn at serine-129 (pSer129-alpha-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-alpha-syn-induced pathological alpha-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-alpha-syn level mainly by maintaining the normal function of ubiquitin-proteasome system (UPS). Furthermore, Sal promoted the clearance of alpha-syn and protected the cell viability mainly through recovered the 20S proteasome activity in WT/A30P-alpha-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-alpha-syn protein level in 6-OHDA-induced impairmental and dysfunctional SH-SY5Y cells. Sal promotes the clearance of alpha-syn and protects the cell viability mainly through recovering the 20S proteasome activity in WT/A30P-alpha-syn plasmids transfected cells. Maintaining the normal function of the UPS may be one of the important mechanisms of Sal in neuroprotective effects.