Remarkable impairment of Wnt/ß-catenin signaling in the brains of the mice infected with scrapie agents.
J Neurochem
; 136(4): 731-740, 2016 Feb.
Article
em En
| MEDLINE
| ID: mdl-26526056
ABSTRACT
Prion diseases are a group of neurodegenerative diseases characterized by neuronal loss and spongiform degeneration, astrogliosis and aggregation of scrapie prion protein (PrPSc ) in the central nervous system (CNS). The Wnt signaling pathway is a highly evolutionarily conserved pathway in eukaryotes that regulates cell proliferation, differentiation and survival. Impairment of Wnt/ß-catenin signaling has been reported in the CNS of various neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. To investigate the functional state of Wnt/ß-catenin signaling in the CNS tissues during the progression of prion disease, the components of Wnt/ß-catenin signaling in the brains of the scrapie agents 139A- and ME7-infected mice were evaluated. Compared with the normal controls, the brain levels of phosphor-ß-catenin (Ser33,37 and Thr41 ) in 139A- and ME7-infected mice were significantly increased, while those of cyclin D1, which is one of the target genes of Wnt signaling, were decreased. The levels of phosphor-glycogen synthase kinase-3ß (GSK-3ß) Ser9 were markedly reduced, representing an enhanced GSK-3ß activity in scrapie-infected mice. Both western blot and immunohistochemical assays revealed a remarkable increase of Dickkopf-1, the antagonist of Wnt/ß-catenin signaling, in the brains of scrapie-infected anim-als, which co-localized well with the remaining neurons in the immunofluorescent tests. We also observed slightly decreased Wnt-3 and unchanged disheveled-3 (Dvl-3) in the brains of the infected mice. Our data, here, strongly indicate an impairment of Wnt/ß-catenin pathway in the brains of prion disease, which shows a time-dependent progression along with the incubation period. Schematic for the impairment of canonical Wnt signaling during prion infection. The left and right parts represent the normal and prion-infected situations, respectively. Prion infection or PrPSc accumulation triggers the over-expression of Dickkopf WNT signaling pathway inhibitor 1 (DKK-1) and the enhancement of glycogen synthase kinase 3ß (GSK-3ß) activity, which subsequently promotes the phosphorylation and degradation of ß-catenin. As a result, the impairment of ß-catenin signaling leads to the down-regulation of Wnt target genes.
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01-internacional
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MEDLINE
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En
Ano de publicação:
2016
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Article