The Parkinson\u2019s Disease-Linked Protein DJ-1 Associates with Cytoplasmic mRNP Granules During Stress and Neurodegeneration

Mariaelena Repici,Sara Cimini,Kathryn S Lilley,Tiago F Outeiro,Mahdieh Hassanjani,Bhavini Patel,Flaviano Giorgini,Pedro Garção,Daniel C Maddison,Kornelis R Straatman,Tiziana Borsello,Lia Panman,Éva M Szegö

doi:10.1007/s12035-018-1084-y

Abstract

Mutations in the gene encoding DJ-1 are associated with autosomal recessive forms of Parkinson’s disease (PD). DJ-1 plays a role in protection from oxidative stress, but how it functions as an “upstream” oxidative stress sensor and whether this relates to PD is still unclear. Intriguingly, DJ-1 may act as an RNA binding protein associating with specific mRNA transcripts in the human brain. Moreover, we previously reported that the yeast DJ-1 homolog Hsp31 localizes to stress granules (SGs) after glucose starvation, suggesting a role for DJ-1 in RNA dynamics. Here, we report that DJ-1 interacts with several SG components in mammalian cells and localizes to SGs, as well as P-bodies, upon induction of either osmotic or oxidative stress. By purifying the mRNA associated with DJ-1 in mammalian cells, we detected several transcripts and found that subpopulations of these localize to SGs after stress, suggesting that DJ-1 may target specific mRNAs to mRNP granules. Notably, we find that DJ-1 associates with SGs arising from N-methyl-d-aspartate (NMDA) excitotoxicity in primary neurons and parkinsonism-inducing toxins in dopaminergic cell cultures. Thus, our results indicate that DJ-1 is associated with cytoplasmic RNA granules arising during stress and neurodegeneration, providing a possible link between DJ-1 and RNA dynamics which may be relevant for PD pathogenesis.

Highlights

DJ-1 is encoded by PARK7, a gene associated with autosomal recessive forms of Parkinson’s disease (PD)
Purified proteins were separated by SDSPAGE, stained with Coomassie and each gel lane excised into equal-sized segments and in-gel digested with trypsin, before analysis of the resulting extracted peptides via liquid chromatography tandem-mass spectrometry (LC-MS/MS)
We found that several universal stress granules (SGs) markers are DJ-1 interactors in both control and oxidative stress conditions (e.g., eIF4A3, a splicing factor core component of the exon junction complex (EJC) [26], and the 40S ribosomal proteins S25, S3, and S7)

Summary

Introduction

DJ-1 is encoded by PARK7, a gene associated with autosomal recessive forms of Parkinson’s disease (PD). Mol Neurobiol (2019) 56:61–77 residues implicated in a variety of cellular roles, including response to oxidative stress, mitochondrial health, protein chaperone activity, and regulation of autophagy [3, 4]. This plethora of DJ-1 functions makes it difficult to discern the key molecular mechanisms that connect DJ-1 to PD pathogenesis. The association of DJ-1 with specific mRNA transcripts has been demonstrated in human brain, alongside an alteration in their corresponding protein levels in PD brains [8]. We have recently made the observation that Hsp, a yeast DJ-1 homolog, is localized to stress granules (SGs) and P-bodies (PBs) after glucose starvation and that its deletion influences formation of these cytoplasmic mRNP granules [9]

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Results

Conclusion