Reactive Oxygen Species-Mediated DJ-1 Monomerization Modulates Intracellular Trafficking Involving Karyopherin β2

Abstract

Mutations in DJ-1 are a cause of recessive, early-onset Parkinson's disease (PD). Although oxidative stress and mitochondrial integrity have been implicated in PD, it is largely unknown why neurons degenerate. DJ-1 is involved in oxidative stress-mediated responses and in mitochondrial maintenance; however, its specific function remains vague. Here we show that DJ-1 exhibits neuronal dynamic intracellular trafficking, with dimeric/monomeric cycling modulated by the oxidative environment. We demonstrate that oxidative stress enhances monomerization of wild-type cytosolic DJ-1, leading to nuclear recruitment. The pathogenic DJ-1/E163K variant is unable to homodimerize but is retained in the cytosol upon wild-type DJ-1 heterodimerization. We found that this wild-type/pathogenic heterodimer is disrupted by oxidative stress, leading to DJ-1/E163K mitochondrial translocation. We further demonstrated that endogenously expressed wild-type DJ-1 is imported into neuronal nuclei as a monomer and that nucleo-cytoplasmic transport is oxidative stress mediated. We identified a novel proline-tyrosine nuclear localization signal (PY-NLS) in DJ-1, and we found that nuclear monomeric DJ-1 import is mediated by an oxidative stress-dependent interaction with karyopherin β2. Our study provides evidence that oxidative stress-mediated intracellular trafficking of DJ-1, mediated by dynamic DJ-1 dimeric/monomeric cycling, is implicated in PD pathogenesis.

ACKNOWLEDGMENTS

This work was supported by a grant from the Western Norway Regional Health Authority (Helse Vest project grant 911575).

We thank Lara Aqrawi for expert technical assistance. We thank Darren Moore (Brain Mind Institute, EPFL, Switzerland) for the rabbit monoclonal anti-DJ-1 antibody (N01A), Huaibin Cai (National Institute on Aging, NIH, Bethesda, MD) for DJ-1^−/− MEF cells, Michael J. Courtney (Department of Neurobiology, A. I. Virtanen Institute, University of Eastern Finland) for COX8-dsRed2, and Mike Ryan (Department of Biochemistry, La Trobe University, Australia) for TOM7-GFP.

We have no conflict of interest.