Melatonin rescues zebrafish embryos from the parkinsonian phenotype restoring the parkin/PINK1/DJ-1/MUL1 network Díaz Casado, María Elena Lima, Elena García, José A. Doerrier, Carolina Aranda Martínez, Paula Sayed, Ramy K. A. Guerra Librero Rite, Ana Escames Rosa, Germaine López, Luis C. Acuña Castroviejo, Darío This study was partially supported by grants from the Instituto de Salud Carlos III (Ministerio de Economía y Competitividad and Fondos Feder, Spain n° RD12/0043/0005, PI08-1664; PI13-00981) and from the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía (P07-CTS-03135, and P10-CTS-5784), Spain. The authors thank Iryna Rusanova for her technical support. MED-C is a PhD student supported by the Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Spain; JAG was supported by the Instituto de Salud Carlos III, Spain; CD current address: postdoctoral fellow at the Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, Austria; AG-L is a PhD student supported by the Ministerio de Economía y Competitividad, Spain; and LCL is supported by the ‘Ramón y Cajal’ National Program (Ministerio de Economía y Competitividad, Spain). 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. 2024-11-28T10:47:41Z 2024-11-28T10:47:41Z 2016-04-11 journal article Díaz-Casado et al. Melatonin recovers zebrafish parkinsonian phenotype. J. Pineal Res. 2016; 61:96–107 Doi:10.1111/jpi.12332 https://hdl.handle.net/10481/97506 10.1111/jpi.12332 eng open access Wiley