Deficiency in Neuronal TGF-β Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-β Signaling Protects against MPTP Neurotoxicity in Mice
- Ina Tesseur1,
- Andy Nguyen2,
- Betty Chang2,
- Lulin Li2,
- Nathaniel S. Woodling1,
- Tony Wyss-Coray1,3, and
- Jian Luo1,2
- 1Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, and
- 2Palo Alto Veterans Institute for Research and
- 3Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, California 94304
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Author contributions: T.W.-C., and J.L. designed research; I.T., A.N., B.C., L.L., N.S.W., and J.L. performed research; J.L. and I.T. analyzed data; J.L. wrote the paper.
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 STATEMENT We 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.
- Received September 20, 2016.
- Revision received February 23, 2017.
- Accepted March 22, 2017.
- Copyright © 2017 the authors 0270-6474/17/374584-09$15.00/0
