Objective: To study whether Mesencephalic astrocyte-derived neurotrophic factor (MANF) has beneficial effects in parkinson disease and its intracellular mechanisms. 

Background: The distinguishing feature of Parkinson’s disease is due to the degeneration of dopaminergic(DA) neurons. Caenorhabditis elegans (C.elegans) has a defined neural architecture and it has been demonstrated to be a good in vivo model in the study of neurodegenerative diseases. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a novel neuron factor which exhibits a survival-promoting effect to dopaminergic neurons in vitro. However, to date, it remains unclear whether MANF can rescue DA neurons in α-synuclein (α-Syn) model of PD and the neuroprotective mechanisms of MANF on dopaminergic neurons remain unclear.

Methods: 1. We construct neurotoxin/α-synuclein induced dopamine neurodegeneration model and observe the neuronal morphology includes cell body fluorescence, cilia, dendrite, axon, nuclear morphology and the locomotory index includes bending angle, length of worms, omega bending,  speed,  grid counting, track length. 

2. We feeded MANF/α-Syn treated worms on plates seeded with HT115 E.coli bacteria expressing dsRNA for knocking down autophagy and ER stress related genes. Then we observed the dopamine neuron survival rate of 6-OHDA induced worms treated with MANF and locomotory capacity of α-Syn induced worms treated with MANF.

Results: 1. Dopaminergic neurons show time-related degeneration in 6-OHDA and α-synuclein induced model.

2. The abnormal behavior of C. elegans occurs in both two models. Also, the neuronal morphology damaged at first, then the motor symptoms emerged. 

3. MANF has protective effects in two models. At the same time, MANF rescues the function of  dopamine neurons by calcium imaging (shown – [Fig1] ).

4. We screening all of autophagy and ER stress related genes so far identified in C.elegans, and find that almost all genes are involved in the molecular mechanism of MANF (shown – [Fig2] ).

Conclusions: MANF has protective effects in neurotoxin/Human α-Syn-induced PD models by regulating autophagy and ER stress pathway.

References:

1. Nussbaum RL, Ellis CE. Alzheimer’s disease and Parkinson’s disease. N Engl J Med. 2003;348(14):1356-64.
2. Voutilainen MH, Arumäe U, Airavaara M, Saarma M. Therapeutic potential of the endoplasmic reticulum located and secreted CDNF/MANF family of neurotrophic factors in Parkinson’s disease. FEBS Lett. 2015;589(24 Pt A):3739-48.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/manf-protects-dopamine-neurons-and-locomotion-defect-from-neurotoxinhuman-alpha-synuclein-induced-progressive-parkinsons-disease-models-in-c-elegans/