IRE1 promotes neurodegeneration through autophagy-dependent neuron death in the Drosophila model of Parkinson's disease.

Cheng Yan, Jingqi Liu, Jiamei Gao, Ying Sun, Lei Zhang, Haiyun Song, Lei Xue, Lixing Zhan, Guanjun Gao, Zunji Ke, Yong Liu, Jingnan Liu

Cell death & disease 2019 Oct 22

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Abnormal aggregation of misfolded pathological proteins in neurons is a prominent feature of neurodegenerative disorders including Parkinson's disease (PD). Perturbations of proteostasis at the endoplasmic reticulum (ER) triggers ER stress, activating the unfolded protein response (UPR). Chronic ER stress is thought to underlie the death of neurons during the neurodegenerative progression, but the precise mechanism by which the UPR pathways regulate neuronal cell fate remains incompletely understood. Here we report a critical neurodegenerative role for inositol-requiring enzyme 1 (IRE1), the evolutionarily conserved ER stress sensor, in a Drosophila model of PD. We found that IRE1 was hyperactivated upon accumulation of α-synuclein in the fly photoreceptor neurons. Ectopic overexpression of IRE1 was sufficient to trigger autophagy-dependent neuron death in an XBP1-independent, JNK-dependent manner. Furthermore, IRE1 was able to promote dopaminergic neuron loss, progressive locomotor impairment, and shorter lifespan, whereas blocking IRE1 or ATG7 expression remarkably ameliorated the progression of α-synuclein-caused Parkinson's disease. These results provide in vivo evidence demonstrating that the IRE1 pathway drives PD progression through coupling ER stress to autophagy-dependent neuron death.

Citation

Cheng Yan, Jingqi Liu, Jiamei Gao, Ying Sun, Lei Zhang, Haiyun Song, Lei Xue, Lixing Zhan, Guanjun Gao, Zunji Ke, Yong Liu, Jingnan Liu. IRE1 promotes neurodegeneration through autophagy-dependent neuron death in the Drosophila model of Parkinson's disease. Cell death & disease. 2019 Oct 22;10(11):800