IRE1 promotes neurodegeneration through autophagy-dependent neuron death in the Drosophila model of Parkinson\u2019s disease

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

doi:10.1038/s41419-019-2039-6

Abstract

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.

Highlights

Neurodegenerative diseases share a prominent pathological feature of disturbed proteostasis, which is characterized by the accumulation and aggregation of specific misfolded proteins within the affected neurons[1]
We found that inositol-requiring enzyme 1 (IRE1) deficiency markedly rescued α-Syn-evoked retinal degeneration, as shown by 70%, 72%, and 62% of intact ommotidia, respectively, in retina from GMRGal4 > α-SynWT; Ire1-Ri, GMR-Gal4 > α-SynA30P; Ire1-Ri, and GMR-Gal4 > α-SynA53T; Ire1-Ri flies at 30 days of age (Fig. S1a, b)
As a pathological hallmark of Parkinson’s disease (PD), α-synuclein aggregation in Lewy bodies may reflect the ultimate consequence of the cellular machinery that goes awry for disposal of misfolded proteins

Summary

Introduction

Neurodegenerative diseases share a prominent pathological feature of disturbed proteostasis, which is characterized by the accumulation and aggregation of specific misfolded proteins within the affected neurons[1]. These protein-misfolding disorders include Parkinson’s disease (PD), Alzheimer’s disease (AD), Huntington’s disease (HD), prion-related diseases, and amyotrophic lateral sclerosis (ALS)[2]. Perturbations of proteostasis at the ER, i.e. an overload of Official journal of the Cell Death Differentiation Association. Yan et al Cell Death and Disease (2019)10:800 unfolded or misfolded proteins, cause ER stress and activate the adaptive unfolded protein response (UPR)[1]. The UPR program is governed by three evolutionarily conserved ER transmembrane signal transducers, inositol-requiring enzyme 1 (IRE1), protein kinase RNA-

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Conclusion