Premium
Remarkable impairment of Wnt/β‐catenin signaling in the brains of the mice infected with scrapie agents
Author(s) -
Sun Jing,
Wang Hui,
Chen LiNa,
Wang Jing,
Lv Yan,
Yang XiaoDong,
Zhang BaoYun,
Tian Chan,
Shi Qi,
Dong XiaoPing
Publication year - 2016
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.13416
Subject(s) - wnt signaling pathway , biology , gsk 3 , scrapie , lrp5 , signal transduction , catenin , microbiology and biotechnology , cancer research , pathology , medicine , disease , prion protein
Prion diseases are a group of neurodegenerative diseases characterized by neuronal loss and spongiform degeneration, astrogliosis and aggregation of scrapie prion protein (PrP Sc ) 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 ME 7‐infected mice were evaluated. Compared with the normal controls, the brain levels of phosphor‐β‐catenin (Ser 33,37 and Thr 41 ) in 139A‐ and ME 7‐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) Ser 9 were 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 PrP Sc accumulation 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.