title: Peroxisome proliferator-activated receptor-γ (PPARγ) agonist is neuroprotective and stimulates PGC-1α expression and CREB phosphorylation in human dopaminergic neurons.
abstract: Mitochondrial dysfunction has been linked to several neurodegenerative diseases such as Parkinson's disease (PD). Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master gene for mitochondrial biogenesis and has been shown to be neuroprotective in models of PD. In this work we have studied the mechanisms by which peroxisome proliferator-activated receptor-γ (PPARγ) selective agonist N-(2-benzoylphenyl)-O-[2-(methyl-2-pyridinylamino)ethyl]-l-tyrosine hydrate (GW1929) acts on human dopaminergic neurons in culture. Data showed that GW1929 increased the viability of human dopaminergic neurons and protected them against oxidative stress induced by H2O2 and the mitochondrial toxin Rotenone. The enhanced resilience of the neurons was attributed to increased levels of mitochondrial antioxidants and of PGC-1α. GW1929 treatment further increased cell respiration, mitochondrial biogenesis and sirtuin-1 (SIRT1) expression in the human dopaminergic neurons. Phosphorylation of cAMP responsive element-binding protein (CREB) was also robustly increased in GW1929-treated cells. Together these results show that the PPARγ agonist GW1929 influences CREB signaling and PGC-1α activities in the human dopaminergic neurons contributing to an increased cell viability. This supports the view that drugs acting on the PPARγ-PGC-1α signaling in neurons may have beneficial effects in PD and possible also in other brain disorders.
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, PO Box 63, FIN-00014, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mäkelä
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, PO Box 63, FIN-00014, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, Finland.
authors.forename: Timofey V
authors.initials: TV
authors.lastname: Tselykh
authors.affiliation: Department of Veterinary Biosciences, Unit of Biochemistry and Cell Biology, University of Helsinki, PO Box 66, FIN-00014, University of Helsinki, Finland.
authors.forename: Jyrki P
authors.initials: JP
authors.lastname: Kukkonen
authors.affiliation: Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, Finland.
authors.forename: Ove
authors.initials: O
authors.lastname: Eriksson
authors.affiliation: Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, Finland; Clinicum, Division of Child Psychiatry, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Korhonen
authors.affiliation: Medicum, Department of Biochemistry and Developmental Biology, Faculty of Medicine, PO Box 63, FIN-00014, University of Helsinki, Finland; Minerva Foundation Institute for Medical Research, Biomedicum Helsinki 2U, Tukholmankatu 8, FIN-00290, Helsinki, Finland. Electronic address: dan.lindholm@helsinki.fi.
authors.forename: Dan
authors.initials: D
authors.lastname: Lindholm
mesh_terms: D001577:Benzophenones / Q000494:pharmacology*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D001678:Organelle Biogenesis; D047495:PPAR gamma / Q000819:agonists*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation / Q000187:drug effects; D056564:Sirtuin 1 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: D001577:Benzophenones; D017362:Cyclic AMP Response Element-Binding Protein; D018696:Neuroprotective Agents; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D014443:Tyrosine; C447939:SIRT1 protein, human; D056564:Sirtuin 1; C120099:GW 1929
keywords: CREB; Dopaminergic neurons; Mitochondria; PGC-1α; PPARγ; SIRT1