Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 423, Issue 2, Pages 232-248Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2012.06.034
Keywords
Parkinson's disease; DJ-1; autophagy; rotenone; ERK1/2 pathways
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Funding
- National Basic Research Program of China [2011CB504103, 2012CB722407]
- National Natural Science Foundation of China [30970940]
- Natural Science Foundation of Beijing [5102012, 5102007]
- Beijing Municipal Commission of Education [KZ201010025022]
- Key Laboratory for Neurodegenerative Disease of the Ministry of Education [2011SJBX03]
- Beijing Center of Neural Regeneration and Repair
- Beijing Key Laboratory of Brain Major Disorders [2011SJZS02]
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Loss-of-function mutations in the gene encoding the multifunctional protein, DJ-1, have been implicated in the pathogenesis of early-onset familial Parkinson's disease (PD), suggesting that DJ-1 may act as a neuroprotectant for dopaminergic (DA) neurons. Enhanced autophagy may benefit PD by clearing damaged organelles and protein aggregates; thus, we determined if DJ-1 protects DA neurons against mitochondrial dysfunction and oxidative stress through an autophagic pathway. Cultured DA cells (MN9D) overexpressing DJ-1 were treated with the mitochondrial complex I inhibitor, rotenone. In addition, rotenone was injected into the left substantia nigra of rats 4 weeks after injection with a DJ-1 expression vector. Overexpression of DJ-1 protected MN9D cells against apoptosis, significantly enhanced the survival of nigral DA neurons after rotenone treatment in vivo, and rescued rat behavioral abnormalities. Overexpression of DJ-1 enhanced rotenone-evoked expression of the autophagic markers, beclin-1 and LC3II, while transmission electron microscopy and confocal imaging revealed that the ultrastructural signs of autophagy were increased by DJ-1. The neuroprotective effects of DJ-1 were blocked by phosphoinositol kinase and the autophagy inhibitor, 3-methyladenine, and by the ERK pathway inhibitor, U0126. Confocal imaging revealed that the size of p62-positive puncta decreased significantly in DJ-1 overexpression of MN9D cells 12h after rotenone treatment, suggesting that DJ-1 reveals the ability to clear aggregated p62 associated with PD. Factors that control autophagy, including DJ-1, may inhibit rotenone-induced apoptosis and present novel targets for therapeutic intervention in PD. (C) 2012 Published by Elsevier Ltd.
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