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

ABSTRACT: Transforming growth factor-? (TGF-?) plays an important role in the development and maintenance of embryonic dopaminergic (DA) neurons in the midbrain. To study the function of TGF-? signaling in the adult nigrostriatal system, we generated transgenic mice with reduced TGF-? signaling in mature neurons. These mice display age-related motor deficits and degeneration of the nigrostriatal system. Increasing TGF-? 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-? 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-? (TGF-?) signaling promotes Parkinson disease-related pathologies and motor deficits, and increasing TGF-? 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-? signaling as a potential therapy for Parkinson's disease.

SUBMITTER: Tesseur I 

PROVIDER: S-EPMC5413189 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature