PUBLICATION
p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease
- Authors
- Bretaud, S., Allen, C., Ingham, P.W., and Bandmann, O.
- ID
- ZDB-PUB-061227-43
- Date
- 2007
- Source
- Journal of neurochemistry 100(6): 1626-1635 (Journal)
- Registered Authors
- Allen, Claire, Bandmann, Oliver, Ingham, Philip
- Keywords
- none
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Death/drug effects
- Cell Death/genetics
- Disease Models, Animal
- Embryo, Mammalian
- Embryo, Nonmammalian
- Gene Expression Regulation, Developmental/drug effects
- Gene Expression Regulation, Developmental/genetics
- Humans
- Hydrogen Peroxide/pharmacology
- In Situ Hybridization/methods
- In Situ Nick-End Labeling
- Leupeptins/pharmacology
- Nerve Tissue Proteins/deficiency*
- Neurons/drug effects
- Neurons/physiology*
- Neurotoxins/pharmacology
- Parkinson Disease/genetics
- Parkinson Disease/pathology*
- RNA, Messenger/biosynthesis
- Reverse Transcriptase Polymerase Chain Reaction/methods
- Tumor Suppressor Protein p53/physiology*
- Tyrosine 3-Monooxygenase/metabolism
- Zebrafish
- Zebrafish Proteins/deficiency*
- bcl-2-Associated X Protein/metabolism
- PubMed
- 17166173 Full text @ J. Neurochem.
Citation
Bretaud, S., Allen, C., Ingham, P.W., and Bandmann, O. (2007) p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease. Journal of neurochemistry. 100(6):1626-1635.
Abstract
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping