title: Growth/differentiation factor-15 deficiency compromises dopaminergic neuron survival and microglial response in the 6-hydroxydopamine mouse model of Parkinson's disease.
abstract: Growth/differentiation factor-15 (Gdf-15) is a member of the TGF-β superfamily and a pleiotropic, widely distributed cytokine, which has been shown to play roles in various pathologies, including inflammation. Analysis of Gdf-15(-/-) mice has revealed that it serves the postnatal maintenance of spinal cord motor neurons and sensory neurons. In a previous study, exogenous Gdf-15 rescued 6-hydroxydopamine (6-OHDA) lesioned Gdf-15(+/+) nigrostriatal dopaminergic (DAergic) neurons in vitro and in vivo. Whether endogenous Gdf-15 serves the physiological maintenance of nigrostriatal DAergic neurons in health and disease is not known and was addressed in the present study. Stereotactic injection of 6-OHDA into the medial forebrain bundle (MFB) led to a significant decline in the numbers of DAergic neurons in both Gdf-15(+/+) and Gdf-15(-/-) mice over a time-period of 14days. However, this decrease was exacerbated in the Gdf-15(-/-) mice, with only 5.5% surviving neurons as compared to 24% in the Gdf-15(+/+) mice. Furthermore, the microglial response to the 6-OHDA lesion was reduced in Gdf-15(-/-) mice, with significantly lower numbers of total and activated microglia and a differential cytokine expression as compared to the Gdf-15(+/+) mice. Using in vitro models, we could demonstrate the importance of endogenous Gdf-15 in promoting DAergic neuron survival thus highlighting its relevance in a direct neurotrophic supportive role. Taken together, these results indicate the importance of Gdf-15 in promoting survival of DAergic neurons and regulating the inflammatory response post 6-OHDA lesion.
authors.affiliation: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, University of Freiburg, 79104 Freiburg, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104 Freiburg, Germany; Faculty of Biology, University of Freiburg, 79104 Freiburg, Germany. Electronic address: venissa.machado@sgbm.uni-freiburg.de.
authors.forename: Venissa
authors.initials: V
authors.lastname: Machado
authors.affiliation: Department of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany. Electronic address: stefan.haas@uni-rostock.de.
authors.forename: Stefan J-P
authors.initials: SJ
authors.lastname: Haas
authors.affiliation: Institute of Anatomy and Cell Biology, Universitätsmedizin Greifswald, 17487 Greifswald, Germany. Electronic address: oliver.vonbohlen@uni-greifswald.de.
authors.forename: Oliver
authors.initials: O
authors.lastname: von Bohlen Und Halbach
authors.affiliation: Department of Anatomy, Rostock University Medical Center, 18057 Rostock, Germany. Electronic address: andreas.wree@med.uni-rostock.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Wree
authors.affiliation: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, University of Freiburg, 79104 Freiburg, Germany. Electronic address: kerstin.krieglstein@anat.uni-freiburg.de.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Krieglstein
authors.affiliation: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, University of Freiburg, 79104 Freiburg, Germany. Electronic address: ku39@anat.uni-freiburg.de.
authors.forename: Klaus
authors.initials: K
authors.lastname: Unsicker
authors.affiliation: Institute of Anatomy and Cell Biology, Department of Molecular Embryology, University of Freiburg, 79104 Freiburg, Germany. Electronic address: bjoern.spittau@anat.uni-freiburg.de.
authors.forename: Björn
authors.initials: B
authors.lastname: Spittau
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D002452:Cell Count; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D059290:Dopaminergic Neurons / Q000473:pathology*; D055436:Growth Differentiation Factor 15 / Q000172:deficiency* / Q000235:genetics; D066298:In Vitro Techniques; D008636:Mesencephalon / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology*; D016501:Neurites / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000209:etiology / Q000473:pathology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism
chemical_list: D016207:Cytokines; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D053773:Transforming Growth Factor beta1; D009569:Nitric Oxide; D016627:Oxidopamine; D052247:Nitric Oxide Synthase Type II
keywords: 6-OHDA; Dopaminergic neurons; Gdf-15; Microglia; Neuroinflammation; Neurotrophic factors; Nigrostriatal system; Parkinson's disease