title: Zebrafish Parla- and Parlb-deficiency affects dopaminergic neuron patterning and embryonic survival.
abstract: Many genes associated with familial Parkinson's disease contribute to mitochondrial morphology and function. Some of these genes, for example, Pink1 and Parkin, are part of a common pathway. The presenilin-associated rhomboid-like (PARL) gene was recently linked to familial Parkinson's disease. The PARL gene product is found in the inner mitochondrial membrane and cleaves the optic atrophy 1 protein, involved in mitochondrial morphology and apoptosis. In Drosophila, the PARL-related rhomboid-7 gene acts upstream of pink1 and parkin. However, such a genetic relationship is still unknown in vertebrates. Here, we show that the zebrafish genome comprises two parl paralogs: parla and parlb. Morpholino-mediated loss of parla and/or parlb function resulted in mild neurodegeneration, as evidenced by a lower density of dopaminergic neurons. Patterning of dopaminergic neurons was also perturbed in the ventral diencephalon. Morphants exhibited extensive cell death throughout the entire body as well as increased larval mortality. The morphant phenotype could be rescued by injection of human PARL mRNA, but not catalytically inactive PARL, suggesting functional conservation between the human and zebrafish proteins. More importantly, the zebrafish pink1 mRNA as well as the human PINK1 mRNA, but not kinase-dead nor Parkinson's disease-linked mutant PINK1 mRNA, also rescued the morphant phenotype, providing evidence that Parl genes may function upstream of Pink1, as part of a conserved pathway in vertebrates.
authors.affiliation: Center for Advanced Research in Environmental Genomics, Department of Biology, University of Ottawa, Ottawa, Ontario, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Noble
authors.forename: Abid
authors.initials: A
authors.lastname: Ismail
authors.forename: Rafael
authors.initials: R
authors.lastname: Godoy
authors.forename: Yanwei
authors.initials: Y
authors.lastname: Xi
authors.forename: Marc
authors.initials: M
authors.lastname: Ekker
mesh_terms: D000165:Acridine Orange; D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D003001:Cloning, Molecular; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000502:physiology*; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007814:Larva / Q000166:cytology; D045726:Metalloproteases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000172:deficiency* / Q000235:genetics; D060172:Morpholinos / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D016415:Sequence Alignment / Q000379:methods; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D015027:Zebrafish; D029961:Zebrafish Proteins / Q000172:deficiency* / Q000235:genetics*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D000165:Acridine Orange; D050483:Dopamine Plasma Membrane Transport Proteins; D049452:Green Fluorescent Proteins; D045726:Metalloproteases; D024101:Mitochondrial Proteins; D060172:Morpholinos; D011494:Protein Kinases; D012333:RNA, Messenger; D014446:Tyrosine 3-Monooxygenase; D029961:Zebrafish Proteins; D000099202:PTEN-Induced Putative Kinase; C485184:enhanced green fluorescent protein; C485223:PARL protein, human