Wnt signaling as a potential therapeutic target for frontotemporal dementia

Progranulin mutations result in frontotemporal dementia, but the underlying pathophysiology has remained largely unexplained. New data by Geschwind and colleagues in this issue of Neuron uncovered that the Wnt/FZD2 signaling pathway is an early and critical contributor to disease pathology.     

阿尔茨海默病相关的早老蛋白与Notch和Wnt信号通路

自 1 995年发现高度同源的早老蛋白(ｐｒｅｓｅｎｉｌｉｎ ,ＰＳ) 1、2基因突变可导致家族性早发型阿尔茨海默病 (Ａｌｚｈｅｉｍｅｒｄｉｓｅａｓｅ ,ＡＤ)以来 ,目前不仅已证实ＰＳ参与老年斑核心物质β 淀粉样蛋白 (β ａｍｙｌｏｉｄ ,βＡ)的形成 ,还发现ＰＳ是一种多功能蛋白质 ,与细胞内的多种信号转导通路有关。ＰＳ介导Ｎｏｔｃｈ、Ｗｎｔ/Ｗｉｎｇｌｅｓｓ信号转导的机制、及其与ＡＤ病理改变的关系已成为ＡＤ研究领域的一个新的关注点。1 .ＰＳ和Ｎｏｔｃｈ信号通路的关系Ｎｏｔｃｈ信号在神经元发育中有重要作用 ,通过旁侧抑制…     

The Wnt/Ca2+ pathway: a new vertebrate Wnt signaling pathway takes shape

Members of the vertebrate Wnt family have been subdivided into two functional classes according to their biological activities. Some Wnts signal through the canonical Wnt-1/wingless pathway by stabilizing cytoplasmic beta-catenin. By contrast other Wnts stimulate intracellular Ca2+ release and activate two kinases, CamKII and PKC, in a G-protein-dependent manner. Moreover, putative Wnt receptors belonging to the Frizzled gene family have been identified that preferentially couple to the two prospective pathways in the absence of ectopic Wnt ligand and that might account for the signaling specificity of the Wnt pathways. As Ca2+ release was the first described feature of the noncanonical pathway, and as Ca2+ probably plays a key role in the activation of CamKII and PKC, we have named this Wnt pathway the Wnt/Ca2+ pathway.     

Identification of aldolase as a target antigen in Alzheimer's disease

Alzheimer's disease (AD) is the most common human neurodegenerative disease, leading to progressive cognitive decline and eventually death. The prevailing paradigm on the pathogenesis of AD is that abnormally folded proteins accumulate in specific brain areas and lead to neuronal loss via apoptosis. In recent years it has become evident that an inflammatory and possibly autoimmune component exists in AD. Moreover, recent data demonstrate that immunization with amyloid-beta peptide is therapeutically effective in AD. The nature of CNS Ags that are the target of immune attack in AD is unknown. To identify potential autoantigens in AD, we tested sera IgG Abs of AD patients in immunoblots against brain and other tissue lysates. We identified a 42-kDa band in brain lysates that was detected with >50% of 45 AD sera. The band was identified by mass spectrometry to be aldolase A. Western blotting with aldolase using patient sera demonstrated a band of identical size. The Ab reactivity was verified with ELISAs using aldolase. One of 25 elderly control patients and 3 of 30 multiple sclerosis patients showed similar reactivity (p < 0.002). In enzymatic assays, anti-aldolase positive sera were found to inhibit the enzyme's activity, and the presence of the substrate (fructose 1,6-diphosphate) enhanced Ab binding. Immunization of rats and mice with aldolase in complete Freund's adjuvant was not pathogenic. These findings reveal an autoimmune component in AD, point at aldolase as a common autoantigen in this disease, and suggest a new target for potential immune modulation.     

You Wnt some,you lose some: oncogenes in the Wnt signaling pathway

The highly regulated Wnt signaling cascade plays a decisive role during embryonic patterning and cell-fate determination. The inappropriate expression of Wnt target genes, resulting from deregulation of this pathway, is also implicated in tumorigenesis. Thus, regulation of this pathway is of paramount importance. The Wnt signals are extracellularly regulated by a diverse group of antagonists, cofactors and coreceptors. In the cytoplasm, beta-catenin, a key effector of the Wnt signaling cascade, is highly regulated by a large and fascinating complex of proteins. In the nucleus, activation of target genes is regulated by a complex interplay of activators, repressors and other proteins. Recently, new factors in this pathway have been identified and the interplay and mechanisms of action of key players have been better characterized. Collectively, this represents an important step forward in our understanding of the role of Wnt signaling in development and oncogenesis.     

Regulation of beta-catenin signaling in the Wnt pathway

beta-Catenin not only regulates cell to cell adhesion as a protein interacting with cadherin, but also functions as a component of the Wnt signaling pathway. The Wnt signaling pathway is conserved in various organisms from worms to mammals, and plays important roles in development, cellular proliferation, and differentiation. Wnt stabilizes cytoplasmic beta-catenin and then beta-catenin is translocated into the nucleus where it stimulates the expression of genes including c-myc, c-jun, fra-1, and cyclin D1. The amounts and functions of beta-catenin are regulated in both the cytoplasm and nucleus. Its molecular mechanisms are becoming increasingly well understood.     

The Wnt signaling pathway in retinal degenerations

The retina is a complex tissue composed of multiple interconnected cell layers, highly specialized for transforming light and color into electrical signals perceived by the brain. Damage or death of the primary light-sensing cells, the photoreceptors, results in devastating effects on vision. Despite the identification of numerous mutations that cause inherited retinal degenerations, the cellular and molecular mechanisms leading from the primary mutations to photoreceptor apoptosis are not understood. Wnt signaling has essential regulatory functions in a wide variety of critical developmental processes. Our research and others' have suggested that the Wnt pathway may be involved in retinal degeneration. Wnt ligands regulate developmental death of Drosophila photoreceptors, dysregulated Wnt signaling is involved in neuronal degeneration elsewhere in the central nervous system and Wnts control the expression of pro-survival growth factors in mammalian tissues. Additionally, altered expression of Wnt pathway genes, including the anti-apoptotic Wnt signaling regulator Dickkopf 3 (Dkk3), were observed during photoreceptor loss. This review examines the evidence and develops a model proposing a pro-survival role for Wnt signaling during photoreceptor injury. Because manipulating Wnt signaling has been demonstrated to have therapeutic potential for the treatment of Alzheimers disease, understanding the involvement of Wnts in photoreceptor death will determine whether targeting the Wnt pathway should also be considered as a possible therapeutic strategy for retinal degenerations.     

Identification of ptpro as a novel target gene of Wnt signaling and its potential role as a receptor for Wnt

Wnt/β-catenin signaling plays critical roles in embryonic development and tissue homeostasis in adults by controlling the expression of target genes. We found that expression of ptpro, which encodes a protein tyrosine phosphatase receptor type O (PTPRO), was induced by Wnt/β-catenin signaling in a T cell factor/lymphoid enhancer factor dependent manner. Biochemical assays found that PTPRO interacted with Wnt via its extracellular domain. In addition, ectopic expression of this extracellular domain inhibited Wnt-mediated reporter activity. These results suggest that ptpro is a target gene of Wnt/β-catenin signaling and that PTPRO may function as a novel receptor for Wnt.

Structured summary

MINT-7992076: Ptpro (uniprotkb:Q7TSY7) physically interacts (MI:0915) with Wnt3a (uniprotkb:P27467) by anti tag coimmunoprecipitation (MI:0007)MINT-7992094: Ptpro (uniprotkb:Q7TSY7) physically interacts (MI:0915) with Wnt-3a (uniprotkb:P27467) by cross-linking study (MI:0030)     

Wnt/Ca2+ signaling pathway: a brief overview

The non-canonical Wnt/Ca(2+) signaling cascade is less characterized than their canonical counterpart, the Wnt/β-catenin pathway. The non-canonical Wnt signaling pathways are diverse, defined as planer cell polarity pathway, Wnt-RAP1 signaling pathway, Wnt-Ror2 signaling pathway, Wnt-PKA pathway, Wnt-GSK3MT pathway, Wnt-aPKC pathway, Wnt-RYK pathway, Wnt-mTOR pathway, and Wnt/calcium signaling pathway. All these pathways exhibit a considerable degree of overlap between them. The Wnt/Ca(2+) signaling pathway was deciphered as a crucial mediator in development. However, now there is substantial evidence that the signaling cascade is involved in many other molecular phenomena. Many aspects of Wnt/Ca(2+) pathway are yet enigmatic. This review will give a brief overview of the fundamental and evolving concepts of the Wnt/Ca(2+) signaling pathway.     

Akt participation in the Wnt signaling pathway through Dishevelled

Inactivation of glycogen synthase kinase 3beta (GSK3beta) and the resulting stabilization of free beta-catenin are critical steps in the activation of Wnt target genes. While Akt regulates GSK3alpha/beta in the phosphatidylinositide 3-OH kinase signaling pathway, its role in Wnt signaling is unknown. Here we report that expression of Wnt or Dishevelled (Dvl) increased Akt activity. Activated Akt bound to the Axin-GSK3beta complex in the presence of Dvl, phosphorylated GSK3beta and increased free beta-catenin levels. Furthermore, in Wnt-overexpressing PC12 cells, dominant-negative Akt decreased free beta-catenin and derepressed nerve growth factor-induced differentiation. Therefore, Akt acts in association with Dvl as an important regulator of the Wnt signaling pathway.     

Wnt/beta-catenin signaling: a promising new target for fibrosis diseases

Wnt/beta-catenin signaling is involved in virtually every aspect of embryonic development and also controls homeostatic self-renewal in a number of adult tissues. Recently, emerging evidence from researches of organ fibrosis suggest that sustained Wnt/beta-catenin pathway reactivation is linked to the pathogenesis of fibrotic disorders. Here we focus on Wnt/beta-catenin-related pathogenic effects in different organs, such as lung fibrosis, liver fibrosis, skin fibrosis and renal fibrosis. Additionally, Wnt/beta-catenin signaling works in a combinatorial manner with TGF-beta signaling in the process of fibrosis, and TGF-beta signaling can induce expression of Wnt/beta-catenin superfamily members and vice versa. Moreover, network analysis, based on pathway databases, revealed that key factors in the Wnt pathway were targeted by some differentially expressed microRNAs detected in fibrosis diseases. These findings demonstrated the crosstalks between Wnt/beta-catenin pathway and TGF-beta signalings, and microRNAs, highlighting the role of Wnts in organ fibrogenesis. Most importantly, nowadays there is a variety of Wnt pathway inhibitors which give us the potential therapeutic feasibility, modulation of the Wnt pathway may, therefore, present as a suitable and promising therapeutic strategy in the future.     

Cdx4 is a direct target of the canonical Wnt pathway

There is considerable evidence that the Cdx gene products impact on vertebral patterning by direct regulation of Hox gene expression. Data from a number of vertebrate model systems also suggest that Cdx1, Cdx2 and Cdx4 are targets of caudalizing signals such as RA, Wnt and FGF. These observations have lead to the hypothesis that Cdx members serve to relay information from signaling pathways involved in posterior patterning to the Hox genes. Regulation of Cdx1 expression by RA and Wnt in the mouse has been well characterized; however, the means by which Cdx2 and Cdx4 are regulated is less well understood. In the present study, we present data suggesting that Cdx4 is a direct target of the canonical Wnt pathway. We found that Cdx4 responds to exogenous Wnt3a in mouse embryos ex vivo, and conversely, that its expression is down-regulated in Wnt3a(vt/vt) embryos and in embryos cultured in the presence of Wnt inhibitors. We also found that the Cdx4 promoter responds to Wnt signaling in P19 embryocarcinoma cells and have identified several putative LEF/TCF response elements mediating this effect. Consistent with these data, chromatin immunoprecipitation assays from either embryocarcinoma cells or from the tail bud of embryos revealed that LEF1 and beta-catenin co-localize with the Cdx4 promoter. Taken together, these results suggest that Cdx4, like Cdx1, is a direct Wnt target.