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Reactive oxygen spe...
Reactive oxygen species-mediated DJ-1 monomerization modulates intracellular trafficking involving karyopherin beta 2
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- Björkblom, Benny (author)
- The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway ; Center for Organelle Research, University of Stavanger, Stavanger, Norway
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- Maple-Grødem, Jodi (author)
- The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway ; Center for Organelle Research, University of Stavanger, Stavanger, Norway
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- Puno, Marc Rhyan (author)
- Department of Molecular and Applied Biosciences, University of Westminster, London, United Kingdom
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- Odell, Mark (author)
- Department of Molecular and Applied Biosciences, University of Westminster, London, United Kingdom
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- Larsen, Jan Petter (author)
- The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway
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- Møller, Simon Geir (author)
- The Norwegian Center for Movement Disorders, Stavanger University Hospital, Stavanger, Norway ; Department of Biological Sciences, St. John's University, New York, New York, USA
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(creator_code:org_t)
- 2014
- 2014
- English.
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In: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 34:16, s. 3024-3040
- Related links:
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- 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 beta 2. 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.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
Publication and Content Type
- ref (subject category)
- art (subject category)
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