Document Detail


Parkinson's disease-associated DJ-1 mutations impair mitochondrial dynamics and cause mitochondrial dysfunction.
MedLine Citation:
PMID:  22428580     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Mitochondrial dysfunction represents a critical event during the pathogenesis of Parkinson's disease (PD) and expanding evidences demonstrate that an altered balance in mitochondrial fission/fusion is likely an important mechanism leading to mitochondrial and neuronal dysfunction/degeneration. In this study, we investigated whether DJ-1 is involved in the regulation of mitochondrial dynamics and function in neuronal cells. Confocal and electron microscopic analysis demonstrated that M17 human neuroblastoma cells over-expressing wild-type DJ-1 (WT DJ-1 cells) displayed elongated mitochondria while M17 cells over-expressing PD-associated DJ-1 mutants (R98Q, D149A and L166P) (mutant DJ-1 cells) showed significant increase of fragmented mitochondria. Similar mitochondrial fragmentation was also noted in primary hippocampal neurons over-expressing PD-associated mutant forms of DJ-1. Functional analysis revealed that over-expression of PD-associated DJ-1 mutants resulted in mitochondria dysfunction and increased neuronal vulnerability to oxidative stress (H(2) O(2)) or neurotoxin. Further immunoblot studies demonstrated that levels of dynamin-like protein (DLP1), also known as Drp1, a regulator of mitochondrial fission, was significantly decreased in WT DJ-1 cells but increased in mutant DJ-1 cells. Importantly, DLP1 knockdown in these mutant DJ-1 cells rescued the abnormal mitochondria morphology and all associated mitochondria/neuronal dysfunction. Taken together, these studies suggest that DJ-1 is involved in the regulation of mitochondrial dynamics through modulation of DLP1 expression and PD-associated DJ-1 mutations may cause PD by impairing mitochondrial dynamics and function.
Authors:
Xinglong Wang; Timothy G Petrie; Yingchao Liu; Jun Liu; Hisashi Fujioka; Xiongwei Zhu
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-12
Journal Detail:
Title:  Journal of neurochemistry     Volume:  121     ISSN:  1471-4159     ISO Abbreviation:  J. Neurochem.     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-02     Completed Date:  2012-06-22     Revised Date:  2013-08-14    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  830-9     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.
Affiliation:
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. xiongwei.zhu@case.edu
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MeSH Terms
Descriptor/Qualifier:
Blotting, Western
Cell Line
Fluorescent Antibody Technique
GTP Phosphohydrolases / genetics,  metabolism*
Humans
Intracellular Signaling Peptides and Proteins / genetics*,  metabolism
Microscopy, Confocal
Microscopy, Electron, Transmission
Microtubule-Associated Proteins / genetics,  metabolism*
Mitochondria / genetics,  metabolism*,  ultrastructure*
Mitochondrial Proteins / genetics,  metabolism*
Mutation*
Oncogene Proteins / genetics*,  metabolism
Parkinson Disease / genetics*,  metabolism,  pathology
Transfection
Grant Support
ID/Acronym/Agency:
R21 NS071184/NS/NINDS NIH HHS; R21 NS071184/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Intracellular Signaling Peptides and Proteins; 0/Microtubule-Associated Proteins; 0/Mitochondrial Proteins; 0/Oncogene Proteins; 0/PARK7 protein, human; EC 3.6.1.-/GTP Phosphohydrolases; EC 3.6.5.5/DNM1L protein, human
Comments/Corrections

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