Document Detail

p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease.
MedLine Citation:
PMID:  17166173     Owner:  NLM     Status:  MEDLINE    
Mutations in DJ-1 lead to early onset Parkinson's disease (PD). The aim of this study was to elucidate further the underlying mechanisms leading to neuronal cell death in DJ-1 deficiency in vivo and determine whether the observed cell loss could be prevented pharmacologically. Inactivation of DJ-1 in zebrafish, Danio rerio, resulted in loss of dopaminergic neurons after exposure to hydrogen peroxide and the proteasome inhibitor MG132. DJ-1 knockdown by itself already resulted in increased p53 and Bax expression levels prior to toxin exposure without marked neuronal cell death, suggesting subthreshold activation of cell death pathways in DJ-1 deficiency. Proteasome inhibition led to a further increase of p53 and Bax expression with widespread neuronal cell death. Pharmacological p53 inhibition either before or during MG132 exposure in vivo prevented dopaminergic neuronal cell death in both cases. Simultaneous knockdown of DJ-1 and the negative p53 regulator mdm2 led to dopaminergic neuronal cell death even without toxin exposure, further implicating involvement of p53 in DJ-1 deficiency-mediated neuronal cell loss. Our study demonstrates the utility of zebrafish as a new animal model to study PD gene defects and suggests that modulation of downstream mechanisms, such as p53 inhibition, may be of therapeutic benefit.
Sandrine Bretaud; Claire Allen; Phillip W Ingham; Oliver Bandmann
Related Documents :
19737973 - Pharmacologic p53 activation blocks cell cycle progression but fails to induce senescen...
17912033 - Replication stress, defective s-phase checkpoint and increased death in plk2-deficient ...
1834683 - Possible roles for tgf beta 1 in the gastrulating chick embryo.
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-12-12
Journal Detail:
Title:  Journal of neurochemistry     Volume:  100     ISSN:  0022-3042     ISO Abbreviation:  J. Neurochem.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-03-09     Completed Date:  2007-05-01     Revised Date:  2012-01-13    
Medline Journal Info:
Nlm Unique ID:  2985190R     Medline TA:  J Neurochem     Country:  England    
Other Details:
Languages:  eng     Pagination:  1626-35     Citation Subset:  IM    
Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, UK.
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Animals, Genetically Modified
Cell Death / drug effects,  genetics
Disease Models, Animal
Embryo, Mammalian
Embryo, Nonmammalian
Gene Expression Regulation, Developmental / drug effects,  genetics
Hydrogen Peroxide / pharmacology
In Situ Hybridization / methods
In Situ Nick-End Labeling
Leupeptins / pharmacology
Nerve Tissue Proteins / deficiency*
Neurons / drug effects,  physiology*
Neurotoxins / pharmacology
Parkinson Disease / genetics,  pathology*
RNA, Messenger / biosynthesis
Reverse Transcriptase Polymerase Chain Reaction / methods
Tumor Suppressor Protein p53 / physiology*
Tyrosine 3-Monooxygenase / metabolism
Zebrafish Proteins / deficiency*
bcl-2-Associated X Protein / metabolism
Grant Support
G-0608//Parkinson's UK
Reg. No./Substance:
0/DJ-1 protein, zebrafish; 0/Leupeptins; 0/Nerve Tissue Proteins; 0/Neurotoxins; 0/RNA, Messenger; 0/Tumor Suppressor Protein p53; 0/Zebrafish Proteins; 0/bcl-2-Associated X Protein; 133407-82-6/benzyloxycarbonylleucyl-leucyl-leucine aldehyde; 7722-84-1/Hydrogen Peroxide; EC 3-Monooxygenase

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  DNA fragmentation assessment by flow cytometry and Sperm-Bos-Halomax (bright-field microscopy and fl...
Next Document:  Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: a role for gender.