title: Remarkable impairment of Wnt/β-catenin signaling in the brains of the mice infected with scrapie agents.
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/β-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/β-catenin signaling in the CNS tissues during the progression of prion disease, the components of Wnt/β-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-β-catenin (Ser33,37and 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-3β (GSK-3β) Ser9were markedly reduced, representing an enhanced GSK-3β activity in scrapie-infected mice. Both western blot and immunohistochemical assays revealed a remarkable increase of Dickkopf-1, the antagonist of Wnt/β-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/β-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 PrPScaccumulation triggers the over-expression of Dickkopf WNT signaling pathway inhibitor 1 (DKK-1) and the enhancement of glycogen synthase kinase 3β (GSK-3β) activity, which subsequently promotes the phosphorylation and degradation of β-catenin. As a result, the impairment of β-catenin signaling leads to the down-regulation of Wnt target genes.
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.|Department of Immunology and the key Laboratory of laboratory medicine of Jiangsu province, Jiangsu University Medical School, Zhenjiang, Jiangsu, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Chen
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lv
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Xiao-Dong
authors.initials: XD
authors.lastname: Yang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Bao-Yun
authors.initials: BY
authors.lastname: Zhang
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Chan
authors.initials: C
authors.lastname: Tian
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Shi
authors.affiliation: State Key Laboratory for Infectious Disease Prevention and Control, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases (Zhejiang University, Hangzhou 310003), National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China.|Chinese Academy of Sciences Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Xiao-Ping
authors.initials: XP
authors.lastname: Dong
keywords: DKK-1; GSK-3β; Prion diseases; Wnt/β-catenin signaling; scrapie; β-catenin