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Reactive oxygen species-mediated DJ-1 monomerization modulates intracellular trafficking involving karyopherin β2

Benny Björkblom1, Jodi Maple-Grødem2, Marc Rhyan Puno3

  • 1The 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.

Molecular and Cellular Biology
|June 11, 2014
PubMed

Insights

Mutations in the DJ-1 gene cause Parkinson's disease (PD). Oxidative stress alters DJ-1's movement within neurons, affecting its function and contributing to neurodegeneration in PD.

Area of Science:

  • Neuroscience
  • Genetics
  • Cell Biology

Background:

  • Mutations in DJ-1 are linked to early-onset Parkinson's disease (PD).
  • Oxidative stress and mitochondrial dysfunction are implicated in PD pathogenesis.
  • The precise function of DJ-1 in neuronal degeneration remains unclear.

Purpose of the Study:

  • To investigate the role of DJ-1's intracellular trafficking in Parkinson's disease.
  • To elucidate how oxidative stress influences DJ-1's localization and function.
  • To identify mechanisms underlying DJ-1-related neurodegeneration.

Main Methods:

  • Studied DJ-1's dynamic intracellular trafficking in neurons.
  • Analyzed DJ-1 monomeric/dimeric cycling under varying oxidative conditions.
  • Investigated the interaction of wild-type and pathogenic DJ-1 variants with cellular compartments.
  • Identified a novel proline-tyrosine nuclear localization signal (PY-NLS) in DJ-1.

Main Results:

  • Oxidative stress promotes monomerization of wild-type DJ-1, leading to nuclear import.
  • A pathogenic DJ-1 variant (DJ-1/E163K) is translocated to mitochondria under oxidative stress.
  • Nuclear import of monomeric DJ-1 is mediated by karyopherin β2 in an oxidative stress-dependent manner.
  • DJ-1's nucleo-cytoplasmic transport is regulated by the oxidative environment.

Conclusions:

  • Oxidative stress-mediated intracellular trafficking of DJ-1, driven by dynamic monomer-dimer cycling, plays a significant role in Parkinson's disease pathogenesis.
  • Understanding DJ-1's trafficking provides insights into neurodegenerative mechanisms in PD.
  • Targeting DJ-1's oxidative stress-dependent transport may offer therapeutic strategies for PD.

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