title: 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.
authors.affiliation: The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway Center for Organelle Research, University of Stavanger, Stavanger, Norway benny.bjorkblom@chem.umu.se mollers@stjohns.edu.
authors.forename: Benny
authors.initials: B
authors.lastname: Björkblom
authors.affiliation: The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway Center for Organelle Research, University of Stavanger, Stavanger, Norway.
authors.forename: Jodi
authors.initials: J
authors.lastname: Maple-Grødem
authors.affiliation: Department of Molecular and Applied Biosciences, University of Westminster, London, United Kingdom.
authors.forename: Marc Rhyan
authors.initials: MR
authors.lastname: Puno
authors.affiliation: Department of Molecular and Applied Biosciences, University of Westminster, London, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Odell
authors.affiliation: The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway.
authors.forename: Jan Petter
authors.initials: JP
authors.lastname: Larsen
authors.affiliation: The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway Department of Biological Sciences, St. John's University, New York, New York, USA benny.bjorkblom@chem.umu.se mollers@stjohns.edu.
authors.forename: Simon Geir
authors.initials: SG
authors.lastname: Møller
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D005260:Female; D006801:Humans; D051379:Mice; D008928:Mitochondria; D009474:Neurons / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D054464:Peroxiredoxins; D000071617:Protein Deglycase DJ-1; D021381:Protein Transport / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics; D028961:beta Karyopherins / Q000378:metabolism*
chemical_list: D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; C108121:TNPO1 protein, human; D028961:beta Karyopherins; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1