title: Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1.
abstract: BACKGROUND
  Mitochondrial dysfunction and degradation takes a central role in current paradigms of neurodegeneration in Parkinson's disease (PD). Loss of DJ-1 function is a rare cause of familial PD. Although a critical role of DJ-1 in oxidative stress response and mitochondrial function has been recognized, the effects on mitochondrial dynamics and downstream consequences remain to be determined.
  
  
  RESULTS
  Using DJ-1 loss of function cellular models from knockout (KO) mice and human carriers of the E64D mutation in the DJ-1 gene we define a novel role of DJ-1 in the integrity of both cellular organelles, mitochondria and lysosomes. We show that loss of DJ-1 caused impaired mitochondrial respiration, increased intramitochondrial reactive oxygen species, reduced mitochondrial membrane potential and characteristic alterations of mitochondrial shape as shown by quantitative morphology. Importantly, ultrastructural imaging and subsequent detailed lysosomal activity analyses revealed reduced basal autophagic degradation and the accumulation of defective mitochondria in DJ-1 KO cells, that was linked with decreased levels of phospho-activated ERK2.
  
  
  CONCLUSIONS
  We show that loss of DJ-1 leads to impaired autophagy and accumulation of dysfunctional mitochondria that under physiological conditions would be compensated via lysosomal clearance. Our study provides evidence for a critical role of DJ-1 in mitochondrial homeostasis by connecting basal autophagy and mitochondrial integrity in Parkinson's disease.
authors.affiliation: Center of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors.forename: Guido
authors.initials: G
authors.lastname: Krebiehl
authors.forename: Sabine
authors.initials: S
authors.lastname: Ruckerbauer
authors.forename: Lena F
authors.initials: LF
authors.lastname: Burbulla
authors.forename: Nicole
authors.initials: N
authors.lastname: Kieper
authors.forename: Brigitte
authors.initials: B
authors.lastname: Maurer
authors.forename: Jens
authors.initials: J
authors.lastname: Waak
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Zemfira
authors.initials: Z
authors.lastname: Gizatullina
authors.forename: Frank N
authors.initials: FN
authors.lastname: Gellerich
authors.forename: Dirk
authors.initials: D
authors.lastname: Woitalla
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.forename: Philipp J
authors.initials: PJ
authors.lastname: Kahle
authors.forename: Tassula
authors.initials: T
authors.lastname: Proikas-Cezanne
authors.forename: Rejko
authors.initials: R
authors.lastname: Krüger
mesh_terms: D000818:Animals; D001343:Autophagy; D015153:Blotting, Western; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D008928:Mitochondria / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D010085:Oxidative Phosphorylation; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology; D054464:Peroxiredoxins; D010766:Phosphorylation; D000071617:Protein Deglycase DJ-1; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D015513:Oncogene Proteins; D017382:Reactive Oxygen Species; D054464:Peroxiredoxins; D019950:Mitogen-Activated Protein Kinase 1; C105131:PARK7 protein, human; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1