Peiminine Reduces ARTS-Mediated Degradation of XIAP by Modulating the PINK1/Parkin Pathway to Ameliorate 6-Hydroxydopamine Toxicity and α-Synuclein Accumulation in Parkinson's Disease Models In Vivo and In Vitro.

Yu-Ling Hsu,Shinn-Zong Lin,Woei-Cherng Shyu,Shih-Ping Liu,Ru-Huei Fu,Huey-Shan Hung,Chia-Wen Tsai,Yun-Hua Kuo,Yu-Ting Chiang

doi:10.3390/ijms221910240

Abstract

Parkinson’s disease (PD) is a degenerative disease that can cause motor, cognitive, and behavioral disorders. The treatment strategies being developed are based on the typical pathologic features of PD, including the death of dopaminergic (DA) neurons in the substantia nigra of the midbrain and the accumulation of α-synuclein in neurons. Peiminine (PMN) is an extract of Fritillaria thunbergii Miq that has antioxidant and anti-neuroinflammatory effects. We used Caenorhabditis elegans and SH-SY5Y cell models of PD to evaluate the neuroprotective potential of PMN and address its corresponding mechanism of action. We found that pretreatment with PMN reduced reactive oxygen species production and DA neuron degeneration caused by exposure to 6-hydroxydopamine (6-OHDA), and therefore significantly improved the DA-mediated food-sensing behavior of 6-OHDA-exposed worms and prolonged their lifespan. PMN also diminished the accumulation of α-synuclein in transgenic worms and transfected cells. In our study of the mechanism of action, we found that PMN lessened ARTS-mediated degradation of X-linked inhibitor of apoptosis (XIAP) by enhancing the expression of PINK1/parkin. This led to reduced 6-OHDA-induced apoptosis, enhanced activity of the ubiquitin–proteasome system, and increased autophagy, which diminished the accumulation of α-synuclein. The use of small interfering RNA to down-regulate parkin reversed the benefits of PMN in the PD models. Our findings suggest PMN as a candidate compound worthy of further evaluation for the treatment of PD.

Highlights

Parkinson disease (PD) is a degenerative disease of dopamine neurons caused by environmental or genetic factors that most often occurs in adults older than 60 years
Observation with a dissecting microscope showed that the offspring decreased in number and body size, which reflects the toxicity of PMN and a significant reduction in E. coli consumption
Using RNAi to down-regulate the parkin expression of cells, we found that the ability of PMN to reverse the diminished expression of X-linked inhibitor of apoptosis (XIAP) induced by overexpression of α-synuclein was abolished (Figure 12)

Summary

Introduction

Parkinson disease (PD) is a degenerative disease of dopamine neurons caused by environmental or genetic factors that most often occurs in adults older than 60 years. Loss of dopaminergic (DA) neurons in the substantia nigra compact area of the midbrain is a typical pathologic feature of PD, which results in a lack of dopamine in the basal ganglia and eventually leads to the onset of clinical symptoms, such as bradykinesia, rigidity, tremors, unstable posture, and cognitive and behavioral problems [2]. Another common and important feature of PD pathology is the accumulation of insoluble cytoplasmic α-synuclein, and the formation of Lewy bodies and Lewy neurites in neurons. This replacement results in misfolding and aggregation of α-synuclein to form oligomers or fibrils, which may be related to sporadic PD, with the end result being dysregulation of the synaptic, mitochondrial, and protein homeostasis systems; oxidative stress; microtubule damage; and abnormal calcium signaling [5]

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Conclusion