The molecular basis of copper-transport diseases

Copper (Cu) is a potentially toxic yet essential element. Menkes disease, a copper deficiency disorder, and Wilson disease, a copper toxicosis condition, are two human genetic disorders, caused by mutations of two closely related Cu-transporting ATPases. Both molecules efflux copper from cells. Quite diverse clinical phenotypes are produced by different mutations of these two Cu-transporting proteins. The understanding of copper homeostasis has become increasingly important in clinical medicine as the metal could be involved in the pathogenesis of some important neurological disorders such as Alzheimer's disease, motor neurone diseases and prion diseases.

The molecular basis of copper homeostasis and copper-related disorders

Copper is an essential trace element that can be extremely toxic in excess due to the pro-oxidant activity of copper ions. Inherited disorders of copper transport, Menkes disease (copper deficiency), and Wilson disease (copper toxicosis) are caused by mutations of two closely related Cu transporting-ATPases, and demonstrate the essentiality and potential toxicity of copper. Other copper toxicosis conditions in humans and animals have been described, but are not well understood at a molecular level. Copper homeostatic mechanisms are being discovered. One such mechanism is copper-induced trafficking of the Cu-ATPases, which allows cells to provide copper to secreted cupro-proteins but also to efflux excess copper. Oxidative damage induced by copper may be involved in the pathogenesis of neurodegenerative conditions such as Alzheimer's disease, familial amyotrophic lateral sclerosis, and prion diseases.

Begging and provisioning of thin-billed prions, Pachyptila belcheri, are related to testosterone and corticosterone

Vigorous begging is usually seen as an expression of parent–offspring conflict over limited resources. Chicks signal need by begging, but the evolution of honest signals requires the signals to be costly. Although some possible costs have been identified, the cost-inducing mechanisms underlying this widely distributed signalling system remain unclear. Because hormones associated with stress and hunger (corticosterone) and aggressive behaviour (testosterone) have deleterious side-effects, signalling costs may be coupled to the expression of such hormones, if they are closely associated with the signal. We tested whether begging in chicks of thin-billed prions (Aves, Procellariiformes) is associated with secretion of corticosterone and testosterone. Prion chicks honestly signalled their nutritional state. Begging increased with decreased body condition, both within and between chicks. Adults responded to more intense begging by delivering larger meals. Chick testosterone levels were positively correlated with measures of begging intensity and the mean body condition of chicks was correlated positively with testosterone and negatively with corticosterone. In a cross-fostering experiment, the change in testosterone and corticosterone between control and experimental periods was positively correlated with the change in begging intensity. This is the first experimental evidence that the control of chick begging by endogenously produced testosterone and corticosterone may form a mechanism controlling parental provisioning in birds, and that chick behaviour can help to explain the variation in growth patterns between individual birds.

Diverse fibrillar peptides directly bind the Alzheimer’s amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation

The Alzheimer’s disease Aβ peptide can increase the levels of cell-associated amyloid precursor protein (APP) in vitro. To determine the specificity of this response for Aβ and whether it is related to cytotoxicity, we tested a diverse range of fibrillar peptides including amyloid-β (Aβ), the fibrillar prion peptides PrP106–126 and PrP178–193 and human islet-cell amylin. All these peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2) in primary cultures of astrocytes and neurons. Specificity was shown by a lack of change to amyloid precursor-like protein 1, τ-1 and cellular prion protein (PrPc) levels. APP and APLP2 levels were elevated only in cultures exposed to fibrillar peptides as assessed by electron microscopy and not in cultures treated with non-fibrillogenic peptide variants or aggregated lipoprotein. We found that PrP106–126 and the non-toxic but fibril-forming PrP178–193 increased APP levels in cultures derived from both wild-type and PrPc-deficient mice indicating that fibrillar peptides up-regulate APP through a non-cytotoxic mechanism and irrespective of parental protein expression. Fibrillar PrP106–126 and Aβ peptides bound recombinant APP and APLP2 suggesting the accumulation of these proteins was mediated by direct binding to the fibrillated peptide. This was supported by decreased APP accumulation following extensive washing of the cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with recombinant APP18–146, the putative fibril binding site, also abrogated the accumulation of APP. These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders.

Lipid rafts and HIV-1 : from viral entry to assembly of progeny virions

Background: Lipid rafts are currently an intensely investigated topic of cell biology. In addition to a demonstrated role in signal transduction of the host cell, lipid rafts serve as entry and exit sites for microbial pathogens and toxins, such as FimH-expressing enterobacteria, influenza virus, measles virus and cholera toxin. Furthermore, caveolae, a specialised form of lipid raft, are required for the conversion of the non-pathogenic prion protein to the pathogenic scrapie isoform.

Objectives: A number of reports have shown, directly or indirectly, that lipid rafts are important at various stages of the human immunodeficiency virus type-1 (HIV-1) replication cycle. The purpose of this paper is to provide a brief overview of the role of membrane-associated lipid rafts in cell biology, and to evaluate how HIV-1 has hijacked this cellular component to support HIV-1 replication. Special sections are devoted to discussing the role of lipid rafts in (1) the entry of HIV-1, (2) signal transduction regulation in HIV-1-infected cells, (3) the trafficking of HIV-1 proteins via lipid rafts during HIV-1 assembly; and a further section discusses the role of cholesterol in mature HIV-1.

Summary: Like a number of other pathogens, HIV-1 has evolved to rely on the host cell lipid rafts to support its propagation during multiple stages of the HIV-1 replication cycle. This review has highlighted the importance of lipid rafts in HIV-1 replication.

Impact of introduced house mice (Mus musculus) on burrowing seabirds on Steeple Jason and Grand Jason Islands, Falklands, South Atlantic

Whilst there is good evidence for negative impacts of introduced rat species on island ecosystems, the effects of house mice (Mus musculus) are generally less well documented. In some situations, introduced house mice can exert severe impacts, particularly where this is the only introduced mammal. Here, we examine the distribution, relative abundance and breeding success of small burrowing seabirds on Steeple Jason Island, Falklands, in relation to habitat types and the distribution of house mice which is the sole introduced mammal species, and we make comparisons with seabird distribution and densities on the neighbouring island of Grand Jason where mice are absent. Grey-backed storm-petrel (Garrodia nereis) and Wilson's storm-petrel (Oceanites oceanicus), which due to their extremely small size are likely to be the most vulnerable to mouse predation, were considerably more abundant on mouse-free Grand Jason than on Steeple Jason. Grey-backed storm-petrel, which are typically associated with tussac grass, avoided this habitat on Steeple Jason where it is associated with high levels of house mouse activity (assessed from the proportion of wax baits gnawed overnight), whereas on mouse-free Grand Jason, there was no such avoidance. Wilson's storm-petrel nesting on Steeple Jason suffered high rates of egg and chick loss. Whilst we found evidence for detrimental impacts of house mice on the two small storm-petrel species, there was no relationship between relative mouse activity levels and the distribution or abundance of the larger thin-billed Prion (Pachyptila belcheri). © 2014 Springer-Verlag Berlin Heidelberg.

Aptamer-targeted oligonucleotide theranostics: a smarter approach for brain delivery and the treatment of neurological diseases

Aptamers represent the novel class of oligonucleotides holding multiple applications in the area of biomedicine. The advancements introduced with the Systematic Evolution of Ligands by EXponential enrichment (SELEX) approach further eased the scope of producing modified aptamers within a short span yet retaining the properties of stability and applicability. In the recent times, aptamers were identified to have the potential for penetrating into the deep human crevices and thus can be utilized in addressing the issues of complex neurological disorders. Considering the specificity and stability enhancement by chemical modifications, aptamer-based nanotechnologies may have great potential for future therapeutics and diagnostics (theranostics). The research community has already witnessed success with the approval of macugen (an anti-vascular endothelial growth factor aptamer) for treating degenerating eye disease, and hopefully those that are in the clinical trials will soon be translated for human application. Herein, we have summarized the aptamer chemistry, aptamer-nanoconjugates and their applications against neurological diseases.