An N-terminal fragment of the prion protein binds to amyloid-ß oligomers and inhibits their neurotoxicity in vivo.

A hallmark of Alzheimer disease (AD) is the accumulation of the amyloid-ß (Aß) peptide in the brain. Considerable evidence suggests that soluble Aß oligomers are responsible for the synaptic dysfunction and cognitive deficit observed in AD. However, the mechanism by which these oligomers exert their neurotoxic effect remains unknown. Recently, it was reported that Aß oligomers bind to the cellular prion protein with high affinity. Here, we show that N1, the main physiological cleavage fragment of the cellular prion protein, is necessary and sufficient for binding early oligomeric intermediates during Aß polymerization into amyloid fibrils. The ability of N1 to bind Aß oligomers is influenced by positively charged residues in two sites (positions 23-31 and 95-105) and is dependent on the length of the sequence between them. Importantly, we also show that N1 strongly suppresses Aß oligomer toxicity in cultured murine hippocampal neurons, in a Caenorhabditis elegans-based assay, and in vivo in a mouse model of Aß-induced memory dysfunction. These data suggest that N1, or small peptides derived from it, could be potent inhibitors of Aß oligomer toxicity and represent an entirely new class of therapeutic agents for AD.

The N-terminal, polybasic region of PrP(C) dictates the efficiency of prion propagation by binding to PrP(Sc).

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 ß-sheet-rich oligomers that bind to PrP(C).

Genomic responses from the estrogen-responsive element-dependent signaling pathway mediated by estrogen receptor alpha are required to elicit cellular alterations.

Estrogen (E2) signaling is conveyed by the transcription factors estrogen receptor (ER) alpha and beta. ERs modulate the expression of genes involved in cellular proliferation, motility, and death. The regulation of transcription by E2-ERalpha through binding to estrogen-responsive elements (EREs) in DNA constitutes the ERE-dependent signaling pathway. E2-ERalpha 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-ERalpha signaling is unclear. To address this issue, we engineered an ERE-binding defective ERalpha mutant (ERalpha(EBD)) by changing residues in an alpha-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-ERalpha(EBD) modulated the expression of a subset of ERalpha-responsive genes identified by microarrays and verified by quantitative PCR. However, E2-ERalpha(EBD) did not affect cell cycle progression, cellular growth, death, or motility in contrast to E2-ERalpha.ERalpha(EBD) in the presence of E2 was also ineffective in inducing phenotypic alterations in ER-negative U-2OS cells derived from an osteosarcoma. E2-ERalpha, 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-ERalpha to induce alterations in cellular responses.

What are comparative studies telling us about the mechanism of ERbeta action in the ERE-dependent E2 signaling pathway?

Estrogen hormone (E2) signaling is primarily conveyed by the estrogen receptors (ER) alpha and beta. 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 ERalpha and ERbeta with specific DNA sequences, the so-called estrogen responsive elements (EREs). This interaction constitutes the initial step in ERE-dependent signaling in which ERbeta is a weaker transcription factor than ERalpha 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 ERbeta, but not that of ERalpha, impairs the ability of the receptor to bind to ERE independent of E2. Although the impaired ERbeta-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 ERbeta, as opposed to that of ERalpha, 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.

Do Estrogen Receptor beta Polymorphisms Play A Role in the Pharmacogenetics of Estrogen Signaling?

Estrogen hormones play critical roles in the regulation of many tissue functions. The effects of estrogens are primarily mediated by the estrogen receptors (ER) alpha and beta. 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 ERalpha 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 ERbeta in order to provide a functional perspective with potential pharmacogenomic implications.