Three novel chromogenic calix[4]arene tetraesters bearing nitrophenol residues which dramatically change their UV–VIS absorbance spectra upon complexation with metal ions have been investigated. Upon addition of metal perchlorates such as lithium or sodium to a solution of the calixarene in tetrahydrofuran, in the presence of a base, a colour change from near colourless to yellow occurs. The colour density is dependent on metal perchlorate concentration and can be monitored by UV–VIS spectroscopy. All three compounds were found to be lithium selective with a 10–40 fold selectivity for lithium against sodium. No colour change was noted in the absence of a base. From two-phase studies, it has been demonstrated that all three ligands have the ability to extract metal ions from an aqueous phase into an immiscible organic phase (butan-1-ol) which had been made basic by the addition of the lipophilic base tridodecylamine, with a colour change from near colourless to yellow occurring in the organic phase. The deprotonated calixarene metal ion complex was found to diffuse into the aqueous phase with time, with the rate of diffusion being strongly dependent on the lipophilic nature of the calixarene backbone.

Calixarene

Chromogenic

Aqueous two-phase system

Tetrahydrofuran

Eriochrome Black T

Metalation

10.1039/p29930001963

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Citations (26)

An inter-domain regulatory mechanism controls toxic activities of PrP^C

Prion (2017)

Alex J. McDonald Bei Wu David A. Harris

The normal function of PrPC, the cellular prion protein, has remained mysterious since its first description over 30 years ago. Amazingly, although complete deletion of the gene encoding PrPC has little phenotypic consequence, expression in transgenic mice of PrP molecules carrying certain internal deletions produces dramatic neurodegenerative phenotypes. In our recent paper, 1 we have demonstrated that the flexible, N-terminal domain of PrPC possesses toxic effector functions, which are regulated by a docking interaction with the structured, C-terminal domain. Disruption of this inter-domain interaction, for example by deletions of the hinge region or by binding of antibodies to the C-terminal domain, results in abnormal ionic currents and degeneration of dendritic spines in cultured neuronal cells. This mechanism may contribute to the neurotoxicity of PrPSc and possibly other protein aggregates, and could play a role in the physiological activity of PrPC. These results also provide a warning about the potential toxic side effects of PrP-directed antibody therapies for prion and Alzheimer's diseases.

Neurotoxicity

C-terminus

10.1080/19336896.2017.1384894

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Citations (4)

Prion neurotoxicity

Brain Pathology (2018)

Nhat T. T. Le Bei Wu David A. Harris

Abstract Although the mechanisms underlying prion propagation and infectivity are now well established, the processes accounting for prion toxicity and pathogenesis have remained mysterious. These processes are of enormous clinical relevance as they hold the key to identification of new molecular targets for therapeutic intervention. In this review, we will discuss two broad areas of investigation relevant to understanding prion neurotoxicity. The first is the use of in vitro experimental systems that model key events in prion pathogenesis. In this context, we will describe a hippocampal neuronal culture system we developed that reproduces the earliest pathological alterations in synaptic morphology and function in response to PrP Sc . This system has allowed us to define a core synaptotoxic signaling pathway involving the activation of NMDA and AMPA receptors, stimulation of p38 MAPK phosphorylation and collapse of the actin cytoskeleton in dendritic spines. The second area concerns a striking and unexpected phenomenon in which certain structural manipulations of the PrP C molecule itself, including introduction of N‐terminal deletion mutations or binding of antibodies to C‐terminal epitopes, unleash powerful toxic effects in cultured cells and transgenic mice. We will describe our studies of this phenomenon, which led to the recognition that it is related to the induction of large, abnormal ionic currents by the structurally altered PrP molecules. Our results suggest a model in which the flexible N‐terminal domain of PrP C serves as a toxic effector which is regulated by intramolecular interactions with the globular C‐terminal domain. Taken together, these two areas of study have provided important clues to underlying cellular and molecular mechanisms of prion neurotoxicity. Nevertheless, much remains to be done on this next frontier of prion science.

Neurotoxicity

10.1111/bpa.12694

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Citations (24)

Structure of REV7-R124A complexed with SHLD3(37-73)

Yue Ma Y. Li Bei Wu H. Huang

10.2210/pdb6m7b/pdb

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Citations (0)