title: Deficiency in Neuronal TGF-β Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-β Signaling Protects against MPTP Neurotoxicity in Mice.
abstract: Transforming growth factor-β (TGF-β) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-β signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-β signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-β signaling in the substantia nigra through adeno-associated virus expressing a constitutively active type I receptor significantly reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurodegeneration and motor deficits. These results suggest that TGF-β signaling is critical for adult DA neuron survival and that modulating this signaling pathway has therapeutic potential in Parkinson disease.SIGNIFICANCE STATEMENTWe show that reducing Transforming growth factor-β (TGF-β) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-β signaling reduces neurotoxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a parkinsonism-inducing agent. Our results provide a rationale to pursue a means of increasing TGF-β signaling as a potential therapy for Parkinson's disease.
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, and.
authors.forename: Ina
authors.initials: I
authors.lastname: Tesseur
authors.affiliation: Palo Alto Veterans Institute for Research and.
authors.forename: Andy
authors.initials: A
authors.lastname: Nguyen
authors.affiliation: Palo Alto Veterans Institute for Research and.
authors.forename: Betty
authors.initials: B
authors.lastname: Chang
authors.affiliation: Palo Alto Veterans Institute for Research and.
authors.forename: Lulin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, and.
authors.forename: Nathaniel S
authors.identifier: 0000-0002-0298-3800
authors.initials: NS
authors.lastname: Woodling
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, and twc@stanford.edu jianl@stanford.edu.|Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, California 94304.
authors.forename: Tony
authors.initials: T
authors.lastname: Wyss-Coray
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, and twc@stanford.edu jianl@stanford.edu.|Palo Alto Veterans Institute for Research and.
authors.forename: Jian
authors.identifier: 0000-0002-2064-8467
authors.initials: J
authors.lastname: Luo
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000235:genetics; D020233:Gait Disorders, Neurologic / Q000139:chemically induced / Q000503:physiopathology; D020267:MPTP Poisoning / Q000503:physiopathology*; D018782:Maze Learning; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017072:Neostriatum / Q000503:physiopathology*; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000503:physiopathology*; D004856:Postural Balance; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics; D015398:Signal Transduction; D013378:Substantia Nigra / Q000503:physiopathology*; D016212:Transforming Growth Factor beta / Q000172:deficiency*
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I
keywords: AAV; MPTP; Parkinson's disease; TGF-β