p53-dependent neuronal cell death in a DJ-1-deficient zebrafish model of Parkinson's disease.
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.
Bretaud
Sandrine
S
Centre for Developmental and Biomedical Genetics, University of Sheffield, Sheffield, UK.
Allen
Claire
C
Ingham
Phillip W
PW
Bandmann
Oliver
O
D000818:Animals; D030801:Animals, Genetically Modified; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D017403:In Situ Hybridization / Q000379:methods; D020287:In Situ Nick-End Labeling; D007976:Leupeptins / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000172:deficiency*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000494:pharmacology; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology*; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency*; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D007976:Leupeptins; D009419:Nerve Tissue Proteins; D009498:Neurotoxins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; D051028:bcl-2-Associated X Protein; C515379:park7 protein, zebrafish; D006861:Hydrogen Peroxide; D014446:Tyrosine 3-Monooxygenase; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde