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

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 a-synuclein model. Glial cell line-derived neurotrophic factor (GDNF) and its related neurturin (NRTN) can protect DA neurons in the neurotoxin but not alpha-synuclein animal models of PD, it failed in the clinical trials. Since alpha-synuclein model can better mimic the progression of human PD, in our study we overexpressed MANF specifically in DA neurons by using an a-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 alpha-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.