Remarkable impairment of Wnt/[beta]-catenin signaling in the brains of the mice infected with scrapie agents

• Published in: Journal of neurochemistry 2016-02, Vol.136 (4), p.731
• Main Authors: Sun, Jing, Wang, Hui, Chen, Li-Na, Wang, Jing, Lv, Yan, Yang, Xiao-Dong, Zhang, Bao-Yun, Tian, Chan, Shi, Qi, Dong, Xiao-Ping
• Format: Article
• Language: English
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.13416

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/[beta]-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/[beta]-catenin signaling in the CNS tissues during the progression of prion disease, the components of Wnt/[beta]-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-[beta]-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-3[beta] (GSK-3[beta]) Ser9 were markedly reduced, representing an enhanced GSK-3[beta] activity in scrapie-infected mice. Both western blot and immunohistochemical assays revealed a remarkable increase of Dickkopf-1, the antagonist of Wnt/[beta]-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/[beta]-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 3[beta] (GSK-3[beta]) activity, which subsequently promotes the phosphorylation and degradation of [beta]-catenin. As a result, the impairment of [beta]-catenin signaling leads to the down-regulation of Wnt target genes.