title: Melatonin rescues zebrafish embryos from the parkinsonian phenotype restoring the parkin/PINK1/DJ-1/MUL1 network.
abstract: Multiple studies reporting mitochondrial impairment in Parkinson's disease (PD) involve knockout or knockdown models to inhibit the expression of mitochondrial-related genes, including parkin, PINK1, and DJ-1 ones. Melatonin has significant neuroprotective properties, which have been related to its ability to boost mitochondrial bioenergetics. The meaning and molecular targets of melatonin in PD are yet unclear. Zebrafish are an outstanding model of PD because they are vertebrates, their dopaminergic system is comparable to the nigrostriatal system of humans, and their brains express the same genes as mammals. The exposure of 24 hpf zebrafish embryos to MPTP leads to a significant inhibition of the mitochondrial complex I and the induction of sncga gene, responsible for enhancing γ-synuclein accumulation, which is related to mitochondrial dysfunction. Moreover, MPTP inhibited the parkin/PINK1/DJ-1 expression, impeding the normal function of the parkin/PINK1/DJ-1/MUL1 network to remove the damaged mitochondria. This situation remains over time, and removing MPTP from the treatment did not stop the neurodegenerative process. On the contrary, mitochondria become worse during the next 2 days without MPTP, and the embryos developed a severe motor impairment that cannot be rescued because the mitochondrial-related gene expression remained inhibited. Melatonin, added together with MPTP or added once MPTP was removed, prevented and recovered, respectively, the parkinsonian phenotype once it was established, restoring gene expression and normal function of the parkin/PINK1/DJ-1/MUL1 loop and also the normal motor activity of the embryos. The results show, for the first time, that melatonin restores brain function in zebrafish suffering with Parkinson-like disease.
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: María E
authors.initials: ME
authors.lastname: Díaz-Casado
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Lima
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: García
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Doerrier
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: Aranda
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Department of Anatomy and Embryology, Faculty of Veterinary Medicine, Sohag University, Sohag, Egypt.
authors.forename: Ramy Ka
authors.initials: RK
authors.lastname: Sayed
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Guerra-Librero
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: Germaine
authors.initials: G
authors.lastname: Escames
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.
authors.forename: Luis C
authors.initials: LC
authors.lastname: López
authors.affiliation: Instituto de Biotecnología, Centro de Investigación Biomédica, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Departamento de Fisiología, Facultad de Medicina, Parque Tecnológico de Ciencias de la Salud, Universidad de Granada, Granada, Spain.|Unidad de Gestión Clínica de Laboratorios Clínicos, Hospital Universitario San Cecilio, Granada, Spain.
authors.forename: Darío
authors.initials: D
authors.lastname: Acuña-Castroviejo
mesh_terms: D000818:Animals; D004625:Embryo, Nonmammalian / Q000378:metabolism*; D020267:MPTP Poisoning / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D015027:Zebrafish / Q000235:genetics / Q000378:metabolism*; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*; D000099202:PTEN-Induced Putative Kinase
chemical_list: D008550:Melatonin; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D044767:Ubiquitin-Protein Ligases; D029961:Zebrafish Proteins; C515379:park7 protein, zebrafish; C111567:parkin protein; C558157:Pink1 protein, zebrafish; D000099202:PTEN-Induced Putative Kinase
keywords: 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; mitochondrial complex I; mitochondrial-related genes; parkinson's disease; zebrafish