Echinacoside's nigrostriatal dopaminergic protection against 6-OHDA-Induced endoplasmic reticulum stress through reducing the accumulation of Seipin.

Yajie Zhang,Yang Zhao,Fuqiong Zhou,Jie Ruan,Hongyan Long,Weina Zhu,Yan Lu

doi:10.1111/jcmm.13285

Yajie Zhang, Yang Zhao + Show 5 more

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https://doi.org/10.1111/jcmm.13285

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Abstract

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. Recent epidemiological studies suggest that echinacoside (ECH), a phenylethanoid glycoside found in Cistanche deserticola, has a protective effect against the development of PD. However, the detailed mechanisms of how ECH suppresses neuronal death have not been fully elucidated. In this study, we confirmed that ECH protects nigrostriatal neurons against 6‐hydroxydopamine (6‐OHDA)‐induced endoplasmic reticulum stress (ERS) in vivo and in vitro. ECH rescued cell viability in damaged cells and decreased 6‐OHDA‐induced reactive oxygen species accumulation in vitro. It also rescued tyrosine hydroxylase and dopamine transporter expression in the striatum, and decreased α‐synuclein aggregation following 6‐OHDA treatment in vivo. The validated mechanism of ECH activity was the reduction in the 6‐OHDA‐induced accumulation of seipin (Berardinelli–Seip congenital lipodystrophy 2). Seipin has been shown to be a key molecule related to motor neuron disease and was tightly associated with ERS in a series of in vivo studies. ECH attenuated seipinopathy by promoting seipin degradation via ubiquitination. ERS was relieved by ECH through the Grp94/Bip‐ATF4‐CHOP signal pathway.

Highlights

Parkinson’s disease (PD), the second most common neurodegenerative disorder after Alzheimer’s disease (AD), is characterized by slow progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) [1, 2]
We identified that ECH has a protective effect on nigrostriatal dopaminergic neurons
Bip accumulation induced by 6-OHDA was reversed by administration of the siRNA for seipin. These results indicated that ECH could decrease seipin overexpression induced by 6-OHDA and that seipin accumulation was a crucial factor leading to Endoplasmic reticulum (ER) stress (ERS)

Summary

Introduction

PD, the second most common neurodegenerative disorder after Alzheimer’s disease (AD), is characterized by slow progressive degeneration of dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) [1, 2]. Mitochondrial dysfunction and oxidative stress [4,5,6], abnormal protein accumulation and aggregation [7, 8], impaired protein degradation e.g. the autophagy-lysosomal pathway [9, 10] and ubiquitin-proteasome pathway [11] and inflammatory responses [12] are all involved in the mechanism of cell damage in PD. Endoplasmic reticulum (ER) dysfunction has an important part to play in a range of neurological disorders, including PD [13]. Drugs that interfere with ER stress (ERS) have great therapeutic a 2017 The Authors

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