DJ-1 modulates the unfolded protein response and cell death via upregulation of ATF4 following ER stress

Jungwoo Yang,David S Park,Kwang Soo Kim,Grace O Iyirhiaro,Ruth S Slack,Steve M Callaghan,Woo Jae Kim,Dianbo Qu,Paul C Marcogliese

doi:10.1038/s41419-019-1354-2

Abstract

The unfolded protein response (UPR) triggered by endoplasmic reticulum (ER) stress is a feature of many neurodegenerative diseases including Alzheimer’s disease, Huntington’s disease and Parkinson’s disease (PD). Although the vast majority of PD is sporadic, mutations in a number of genes including PARK7 which encodes the protein DJ-1 have been linked to early-onset, familial PD. In this regard, both PD of sporadic and genetic origins exhibit markers of ER stress-induced UPR. However, the relationship between pathogenic mutations in PARK7 and ER stress-induced UPR in PD pathogenesis remains unclear. In most contexts, DJ-1 has been shown to protect against neuronal injury. However, we find that DJ-1 deficiency ameliorates death in the context of acute ER stress in vitro and in vivo. DJ-1 loss decreases protein and transcript levels of ATF4, a transcription factor critical to the ER response and reduces the levels of CHOP and BiP, its downstream effectors. The converse is observed with DJ-1 over-expression. Importantly, we find that over-expression of wild-type and PD-associated mutant form of PARK7L166P, enhances ER stress-induced neuronal death by regulating ATF4 transcription and translation. Our results demonstrate a previously unreported role for wild-type and mutant DJ-1 in the regulation of UPR and provides a potential link to PD pathogenesis.

Highlights

Parkinson’s disease (PD) is a progressive movement disorder characterized by loss of dopaminergic (DA) neurons in the Substantia Nigra pars compacta (SNpc)
DJ-1 deficiency downregulates basal activating transcription factor 4 (ATF4) levels endoplasmic reticulum (ER) stress-induced unfolded protein response (UPR) signaling in post-mortem brains of patients and animal models of PD has been documented[16]
We found that DJ-1 KO mouse embryonic fibroblasts (MEFs) displayed increased PIRE1, that correlated with a rapid splicing of XBP-1 mRNA during ER stress and increased cleaved ATF6 (Supplementary data 2A, B, D), indicating that DJ-1 deficiency itself triggers ER stress in MEFs

Summary

Introduction

Parkinson’s disease (PD) is a progressive movement disorder characterized by loss of dopaminergic (DA) neurons in the Substantia Nigra pars compacta (SNpc). The majority of PD cases are sporadic, ~10% of PD is familial[3,4]. DJ-1 encoded by PARK7 may be important in both sporadic[5,6,7] and familial PD8. In sporadic PD, DJ-1 shows increased oxidation[9], and is elevated in patient brain and spinal fluid[6,7]. Mutations in PARK7 account for ~1% of LRRK2 upregulates GRP78, a key survival molecule during ER stress[13]. In Drosophila models of PD, mutations in recessive PD genes: Parkin and Pink[1] induce ER stress through activating PERK14.

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Results

Conclusion