title: Overexpression of DJ-1 protects against C2-ceramide-induced neuronal death through activation of the PI3K/AKT pathway and inhibition of autophagy.
abstract: Parkinson's disease (PD) is the second most frequent neurodegenerative disorder. It is characterized by selective degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Early-onset familial forms of PD are associated with mutations in several genes, including parkin, pink1 and dj-1. DJ-1 encodes a protein whose neuroprotective function has not been completely clarified yet. We aim to understand the neuroprotective mechanisms of DJ-1, in particular, DJ-1's involvement in the regulation of the PI3K/PTEN/AKT/mTOR pathway and neuronal autophagy in a neurotoxic context induced by C2-ceramide, by using CAD cells, a murine cathecolaminergic cell line. We demonstrated that C2-ceramide induces CAD cell death associated with decreased phosphorylation of PTEN at Ser380, AKT at Ser473, and mTOR at Ser2448; and increased of autophagic flux (increased LC3-II and autophagosome formation). Additionally, we showed that overexpression of DJ-1 protects against C2-ceramide-induced neuronal death and it is not associated with change in the phosphorylation of mTOR at Ser2448. In conclusion, these data suggest that DJ-1 reinforces the PI3K/AKT survival pathway and inhibits autophagy, probably by a mechanism independent from mTOR.
authors.affiliation: Neuroscience and Cell Death Group, Faculty of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Jenny
authors.initials: J
authors.lastname: Jaramillo-Gómez
authors.affiliation: Neuroscience and Cell Death Group, Faculty of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Andrea
authors.initials: A
authors.lastname: Niño
authors.affiliation: Neuroscience and Cell Death Group, Faculty of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá, Colombia.
authors.forename: Humberto
authors.initials: H
authors.lastname: Arboleda
authors.affiliation: Neuroscience and Cell Death Group, Faculty of Medicine and Institute of Genetics, Universidad Nacional de Colombia, Bogotá, Colombia. Electronic address: gharboledab@unal.edu.co.
authors.forename: Gonzalo
authors.initials: G
authors.lastname: Arboleda
mesh_terms: D000818:Animals; D001343:Autophagy; D002460:Cell Line; D002470:Cell Survival; D051379:Mice; D009474:Neurons / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000633:toxicity; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D015513:Oncogene Proteins; D051059:PTEN Phosphohydrolase; D054464:Peroxiredoxins; D019869:Phosphatidylinositol 3-Kinases; D000071617:Protein Deglycase DJ-1; D051057:Proto-Oncogene Proteins c-akt; D013110:Sphingosine; D058570:TOR Serine-Threonine Kinases; C064769:N-acetylsphingosine; C503466:PARK7 protein, mouse
keywords: Autophagy; C2-ceramide; DJ-1; PI3K/AKT; Parkinson’s disease; mTOR