Article (Scientific journals)
Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1.
Krebiehl, Guido; Ruckerbauer, Sabine; Burbulla, Lena F. et al.
2010In PLoS ONE, 5 (2), p. 9367
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Keywords :
Animals; Autophagy; Blotting, Western; Fibroblasts/cytology/metabolism/ultrastructure; Humans; Intracellular Signaling Peptides and Proteins/genetics/metabolism; Lysosomes/metabolism/ultrastructure; Mice; Mice, Knockout; Microscopy, Electron; Mitochondria/metabolism; Mitogen-Activated Protein Kinase 1/metabolism; Mutation; Oncogene Proteins/genetics/metabolism; Oxidative Phosphorylation; Parkinson Disease/genetics/pathology; Phosphorylation; Reactive Oxygen Species/metabolism
Abstract :
[en] 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. METHODOLOGY/PRINCIPAL FINDINGS: 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/SIGNIFICANCE: 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.
Research center :
- Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group)
Disciplines :
Genetics & genetic processes
Author, co-author :
Krebiehl, Guido
Ruckerbauer, Sabine
Burbulla, Lena F.
Kieper, Nicole
Maurer, Brigitte
Waak, Jens
Wolburg, Hartwig
Gizatullina, Zemfira
Gellerich, Frank N.
Woitalla, Dirk
Riess, Olaf
Kahle, Philipp J.
Proikas-Cezanne, Tassula
KRÜGER, Rejko ;  University of Luxembourg > Faculty of Science, Technology and Communication (FSTC) > Life Science Research Unit
More authors (4 more) Less
Language :
English
Title :
Reduced basal autophagy and impaired mitochondrial dynamics due to loss of Parkinson's disease-associated protein DJ-1.
Publication date :
2010
Journal title :
PLoS ONE
ISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Volume :
5
Issue :
2
Pages :
e9367
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBilu :
since 28 June 2014

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