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J Neurosci. 2017 Apr 26;37(17):4584-4592. doi: 10.1523/JNEUROSCI.2952-16.2017. Epub 2017 Mar 31.

Deficiency in Neuronal TGF-β Signaling Leads to Nigrostriatal Degeneration and Activation of TGF-β Signaling Protects against MPTP Neurotoxicity in Mice.

Author information

1
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, and.
2
Palo Alto Veterans Institute for Research and.
3
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, and twc@stanford.edu jianl@stanford.edu.
4
Center for Tissue Regeneration, Repair and Restoration, VA Palo Alto Health Care System, Palo Alto, California 94304.

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.

KEYWORDS:

AAV; MPTP; Parkinson's disease; TGF-β

PMID:
28363982
PMCID:
PMC5413189
DOI:
10.1523/JNEUROSCI.2952-16.2017
[Indexed for MEDLINE]
Free PMC Article

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