MANF protects dopamine neurons and locomotion defects from a human α-synuclein induced Parkinson's disease model in C. elegans by regulating ER stress and autophagy pathways

• Published in: Experimental neurology 2018-10, Vol.308, p.59-71
• Main Authors: Zhang, Zhuoyu, Shen, Yijue, Luo, Hang, Zhang, Fen, Peng, Dan, Jing, Li, Wu, Yuanyuan, Xia, Xiaofei, Song, Yunping, Li, Wei, Jin, Lingjing
• Format: Article
• Language: English
• Subjects: alpha-Synuclein - metabolism; Animals; Animals, Genetically Modified; Autophagy; Autophagy - physiology; C. elegans; Caenorhabditis elegans; Calcium; Disease Models, Animal; Dopaminergic Neurons - metabolism; Dopaminergic Neurons - pathology; Endoplasmic Reticulum Stress - physiology; ER stress; Humans; Locomotion - physiology; MANF; Nerve Degeneration - metabolism; Nerve Degeneration - pathology; Nerve Degeneration - physiopathology; Nerve Growth Factors - metabolism; Neuroprotection; Neuroprotection - physiology; Parkinson's disease; Parkinsonian Disorders - metabolism; Parkinsonian Disorders - pathology; Parkinsonian Disorders - physiopathology; α-synuclein
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2018.06.016

Many studies have demonstrated that mesencephalic astrocyte-derived neurotrophic factor (MANF) has been shown protective effects on neurotoxin based models of Parkinson's disease (PD). It still remains unclear whether MANF can rescue dopaminergic (DA) neurons in an α-synuclein model. Glial cell line-derived neurotrophic factor (GDNF) and its related neurturin (NRTN) can protect DA neurons in the neurotoxin but not α-synuclein animal models of PD, it failed in the clinical trials. Since α-synuclein model can better mimic the progression of human PD, in our study we overexpressed MANF specifically in DA neurons by using an α-synuclein Caenorhabditis elegans (C. elegans) model. Our results showed MANF alleviated progressive neuronal degeneration and prevented locomotion defects. Indeed, MANF can protect cilia of DA neurons at an early stage, suggested that MANF participated in the whole process of neuronal degeneration. Furthermore, we found MANF facilitated the removal of misfolded α-synuclein proteins and rescued the function of damaged DA neurons. By using RNAi approach, we inhibited ER stress and autophagy related genes and effects of MANF were decreased, which demonstrated ER stress and autophagy pathways were involved in the MANF-mediated neuroprotection. Our study suggests MANF exhibits potential as a neuroprotective agent for PD therapy. •The degeneration of DA neurons occurs before locomotion defects in C. elegans, MANF rescues DA neural degeneration and locomotion defects during all the period of PD progression.•MANF reduces the aggregation of α-synuclein, restores dopamine levels and rescues the function of DA neurons in the α-synuclein C. elegans model of PD.•ER stress and autophagy pathways are involved in MANF-mediated neuroprotection.