Azoramide protects iPSC-derived dopaminergic neurons with PLA2G6 D331Y mutation through restoring ER function and CREB signaling

Minjing Ke,Haitao Zeng,Cheong-Meng Chong,Dajiang Qin,Xiaotong Cen,Xiaoli Yao,Miaodan Huang,Ke Zhang,Huanxing Su,Zhijian Huang,Jia-Hong Lu

doi:10.1038/s41419-020-2312-8

Abstract

The endoplasmic reticulum (ER)-stress-induced cascade events are implicated in Parkinson’s disease (PD). The discovery of drug candidates to protect dopaminergic (DA) neurons from ER-stress-induced oxidative damage is important to resolve the pathological aspects of PD and modify its progress. In this study, we found that a recently identified unfolded protein response (UPR) modulator, azoramide, showed protective effects on patient induced pluripotent stem cells-derived midbrain DA neurons with the homozygous phospholipase A2 group 6 (PLA2G6) D331Y mutant. A series of PD-related cascade events such as ER stress, abnormal calcium homeostasis, mitochondrial dysfunction, increase of reactive oxygen species, and apoptosis were observed in PLA2G6 D331Y mutant DA neurons, whereas azoramide significantly protected PLA2G6 D331Y mutant DA neurons against these events. The beneficial effects of azoramide were abolished by treatment with a cAMP-response element binding protein (CREB) inhibitor. Our results suggest that azoramide is a potential neuroprotectant against DA neuron damage via restoring ER function and the CREB signaling.

Highlights

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder
Derived midbrain DA neurons Familial PD (FPD) PLA2G6D331Y/D331Y patient-derived induced pluripotent stem cells (iPSCs) were established by reprogramming the urine cells from a male patient donor as described previously[18]
We established a model based on phospholipase A2 group 6 (PLA2G6) mutant, patient-iPSC-derived, midbrain DA neurons, and found that the PLA2G6 mutant caused PD-related cascade events in DA neurons, such as imbalance of Ca2+ homeostasis, increase of unfolded protein response (UPR)

Summary

Introduction

Parkinson’s disease (PD) is the second most common age-related neurodegenerative disorder. It is mainly caused by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. The loss of DA neurons leads to a decrease in dopamine, which is a key neurotransmitter for the coordination of motor control and behavior. PD is clinically characterized by motor symptoms called parkinsonism such as tremor, rigidity, bradykinesia, loss of facial expression, and balance problems[1,2,3]. UPR initially restores normal ER function via reducing protein translation, degrading misfolded proteins, and activating signaling pathways to increase expression of molecular chaperones for protein folding[6,7]. If ER stress cannot be restored by UPR and is prolonged, apoptosis is triggered.

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Conclusion