Background: The cellular prion protein (PrPC) could be a toxicity-transducing receptor for amyloid-β (Aβ) oligomers.Results: N1, a naturally occurring fragment of PrPC, binds Aβ oligomers, inhibits their polymerization into fibrils, and suppresses their neurotoxic effects in vitro and in vivo.Conclusion: N1 binds tightly to Aβ oligomers and blocks their neurotoxicity.Significance: Administration of exogenous N1 or related peptides may represent an effective therapy for Alzheimer disease.

Estrogen (E2) signaling is conveyed by the transcription factors estrogen receptor (ER) ␣ and ␤. ERs modulate the expression of genes involved in cellular proliferation, motility, and death. The regulation of transcription by E2-ER␣ through binding to estrogen-responsive elements (EREs) in DNA constitutes the ERE-dependent signaling pathway. E2-ER␣ also modulates gene expression by interacting with transregulators bound to cognate DNA-regulatory elements, and this regulation is referred to as the ERE-independent signaling pathway. The relative importance of the ERE-independent pathway in E2-ER␣ signaling is unclear. To address this issue, we engineered an ERE-binding defective ER␣ mutant (ER␣ EBD ) by changing residues in an ␣-helix of the protein involved in DNA binding to render the receptor functional only through the ERE-independent signaling pathway. Using recombinant adenovirus-infected ER-negative MDA-MB-231 cells derived from a breast adenocarcinoma, we found that E2-ER␣ EBD modulated the expression of a subset of ER␣-responsive genes identified by microarrays and verified by quantitative PCR. However, E2-ER␣ EBD did not affect cell cycle progression, cellular growth, death, or motility in contrast to E2-ER␣. ER␣ EBD in the presence of E2 was also ineffective in inducing phenotypic alterations in ER-negative U-2OS cells derived from an osteosarcoma. E2-ER␣, on the other hand, effectively repressed growth in this cell line. Our findings suggest that genomic responses from the ERE-dependent signaling pathway are required for E2-ER␣ to induce alterations in cellular responses. 17␤-Estradiol (E2),5 as the main circulating estrogen hormone, plays critical roles in the physiology and pathophysiology of many tissues (1, 2). The effects of E2 are primarily mediated by estrogen receptor (ER) ␣ and ␤ (1, 2). ERs display functionally distinct structural features. The amino terminus of ER␣ contains a ligand-independent transactivation function. The central region is the DNA binding domain (DBD). The flexible hinge domain contains a nuclear localization signal and links the DBD domain to the multifunctional carboxyl-terminal ligand binding (LBD) domain. The LBD is involved in ligand binding, dimerization, and ligand-dependent transactivation function.Following synthesis, ER␣ dimerizes and translocates to the nucleus independent of E2 (3). Fractions of the ER␣ population also partition to the perimembrane, cytoplasm, and mitochondria (4). The binding of E2 to ER␣ leads to a major structural reorganization of the LBD that converts the inactive ER␣ to the functionally active form by generating surfaces that support protein-protein interactions (5). The integration of E2-ER␣ signaling generated from various cellular locations is thought to be critical for the regulation of responsive gene expression involved in cellular proliferation, differentiation, motility, and death (4, 6).One of the primary nuclear E2-ER␣ signaling events involves the interaction of E2-ER␣ with specific DNA sequences, known as estrogen-responsive e...

Prion propagation involves a templating reaction in which the infectious form of the prion protein (PrP Sc) binds to the cellular form (PrP C), generating additional molecules of PrP Sc. While several regions of the PrP C molecule have been suggested to play a role in PrP Sc formation based on in vitro studies, the contribution of these regions in vivo is unclear. Here, we report that mice expressing PrP deleted for a short, polybasic region at the N terminus (residues 23–31) display a dramatically reduced susceptibility to prion infection and accumulate greatly reduced levels of PrP Sc. These results, in combination with biochemical data, demonstrate that residues 23–31 represent a critical site on PrP C that binds to PrP Sc and is essential for efficient prion propagation. It may be possible to specifically target this region for treatment of prion diseases as well as other neurodegenerative disorders due to β-sheet-rich oligomers that bind to PrP C.

Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) α and β. ERs are ligand-activated transcription factors that regulate a complex array of genomic events that orchestrate cellular growth, differentiation and death. Although many factors contribute to their etiology, estrogens are thought to be the primary agents for the development and/or progression of target tissue malignancies. Many of the current modalities for the treatment of estrogen target tissue malignancies are based on agents with diverse pharmacology that alter or prevent ER functions by acting as estrogen competitors. Although these compounds have been successfully used in clinical settings, the efficacy of treatment shows variability. An increasing body of evidence implicates ERα polymorphisms as one of the contributory factors for differential responses to estrogen competitors. This review aims to highlight the recent findings on polymorphisms of the lately identified ERβ in order to provide a functional perspective with potential pharmacogenomic implications.

Estrogen hormone (E2) signaling is primarily conveyed by the estrogen receptors (ER) α and β. ERs are encoded by two distinct genes and share varying degrees of domain-specific structural/functional similarities. ERs mediate a complex array of nuclear and non-nuclear events critical for the homeodynamic regulation of various tissue functions. The canonical nuclear signaling involves the interaction of ERα and ERβ with specific DNA sequences, the so-called estrogen responsive elements (EREs). This interaction constitutes the initial step in ERE-dependent signaling in which ERβ is a weaker transcription factor than ERα in response to E2. However, it remains unclear why transactivation potencies of ER subtypes differ. Studies suggest that the amino-terminus, the least conserved structural region, of ERβ, but not that of ERα, impairs the ability of the receptor to bind to ERE independent of E2. Although the impaired ERβ-ERE interaction contributes, it is not sufficient to explain the weak transactivation potency of the receptor. It appears that the lack of transactivation ability and of the capability of the amino-terminus of ERβ, as opposed to that of ERα, to functionally interact with the carboxyl-terminal hormone-dependent activation domain is also critical for the receptor-specific activity. Thus, the structurally distinct amino-termini of ERs are important determinants in defining the function of ER-subtypes in the ERE-dependent pathway. This could differentially affect the physiology and pathophysiology of E2 signaling.

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