Neurometals in the Pathogenesis of Prion Diseases

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Abstract

Prion diseases are progressive and transmissive neurodegenerative diseases. The conformational conversion of normal cellular prion protein (PrP ^C) into abnormal pathogenic prion protein (PrP ^Sc) is critical for its infection and pathogenesis. PrP ^C possesses the ability to bind to various neurometals, including copper, zinc, iron, and manganese. Moreover, increasing evidence suggests that PrP ^C plays essential roles in the maintenance of homeostasis of these neurometals in the synapse. In addition, trace metals are critical determinants of the conformational change and toxicity of PrP ^C. Here, we review our studies and other new findings that inform the current understanding of the links between trace elements and physiological functions of PrP ^C and the neurotoxicity of PrP ^Sc.

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Quantitative ultrastructural analysis of hippocampal excitatory synapses.

T Schikorski, C F Stevens (1997)

From three-dimensional reconstructions of CA1 excitatory synapses in the rodent hippocampus and in culture, we have estimated statistical distributions of active zone and postsynaptic density (PSD) sizes (average area approximately 0.04 micron2), the number of active zones per bouton (usually one), the number of docked vesicles per active zone (approximately 10), and the total number of vesicles per bouton (approximately 200), and we have determined relationships between these quantities, all of which vary from synapse to synapse but are highly correlated. These measurements have been related to synaptic physiology. In particular, we propose that the distribution of active zone areas can account for the distribution of synaptic release probabilities and that each active zone constitutes a release site as identified in the standard quantal theory attributable to Katz (1969).

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The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide

Stephanie J Soscia, James Kirby, Kevin J Washicosky … (2010)

Background The amyloid β-protein (Aβ) is believed to be the key mediator of Alzheimer's disease (AD) pathology. Aβ is most often characterized as an incidental catabolic byproduct that lacks a normal physiological role. However, Aβ has been shown to be a specific ligand for a number of different receptors and other molecules, transported by complex trafficking pathways, modulated in response to a variety of environmental stressors, and able to induce pro-inflammatory activities. Methodology/Principal Findings Here, we provide data supporting an in vivo function for Aβ as an antimicrobial peptide (AMP). Experiments used established in vitro assays to compare antimicrobial activities of Aβ and LL-37, an archetypical human AMP. Findings reveal that Aβ exerts antimicrobial activity against eight common and clinically relevant microorganisms with a potency equivalent to, and in some cases greater than, LL-37. Furthermore, we show that AD whole brain homogenates have significantly higher antimicrobial activity than aged matched non-AD samples and that AMP action correlates with tissue Aβ levels. Consistent with Aβ-mediated activity, the increased antimicrobial action was ablated by immunodepletion of AD brain homogenates with anti-Aβ antibodies. Conclusions/Significance Our findings suggest Aβ is a hitherto unrecognized AMP that may normally function in the innate immune system. This finding stands in stark contrast to current models of Aβ-mediated pathology and has important implications for ongoing and future AD treatment strategies.

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Importance of zinc in the central nervous system: the zinc-containing neuron.

Paula Silva, R Thompson, Logan Frederickson … (2000)

Zinc is essential to the structure and function of myriad proteins, including regulatory, structural and enzymatic. It is estimated that up to 1% of the human genome codes for zinc finger proteins. In the central nervous system, zinc has an additional role as a neurosecretory product or cofactor. In this role, zinc is highly concentrated in the synaptic vesicles of a specific contingent of neurons, called "zinc-containing" neurons. Zinc-containing neurons are a subset of glutamatergic neurons. The zinc in the vesicles probably exceeds 1 mmol/L in concentration and is only weakly coordinated with any endogenous ligand. Zinc-containing neurons are found almost exclusively in the forebrain, where in mammals they have evolved into a complex and elaborate associational network that interconnects most of the cerebral cortices and limbic structures. Indeed, one of the intriguing aspects of these neurons is that they compose somewhat of a chemospecific "private line" of the mammalian cerebral cortex. The present review outlines (1) the methods used to discover, define and describe zinc-containing neurons; (2) the neuroarchitecture and synaptology of zinc-containing neural circuits; (3) the physiology of regulated vesicular zinc release; (4) the "life cycle" and molecular biology of vesicular zinc; (5) the importance of synaptically released zinc in the normal and pathological processes of the cerebral cortex; and (6) the role of specific and nonspecific stressors in the release of zinc.

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Contributors

Byung-Hoon Jeong: Role: Academic Editor

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (iso-abbrev): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: MDPI

ISSN (Electronic): 1422-0067

Publication date (Electronic): 28 January 2021

Publication date Collection: February 2021

Volume: 22

Issue: 3

Electronic Location Identifier: 1267

Affiliations

Department of Bio-Analytical Chemistry, Research Institute of Pharmaceutical Sciences, Faculty of Pharmacy, Musashino University, Tokyo 202-8585, Japan; mnegishi@ 123456musashino-u.ac.jp (M.K.-N.); k-tana@ 123456musashino-u.ac.jp (K.-i.T.)

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[* ]Correspondence: makawa@ 123456musashino-u.ac.jp ; Tel./Fax: +81-42-468-8299

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Masahiro Kawahara https://orcid.org/0000-0002-3334-4235

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Publisher ID: ijms-22-01267

DOI: 10.3390/ijms22031267

PMC ID: 7866166

PubMed ID: 33525334

SO-VID: ef713c87-f147-4981-adcb-a4cbb40f699c

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

Neurometals in the Pathogenesis of Prion Diseases

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Most cited references 120

Quantitative ultrastructural analysis of hippocampal excitatory synapses.

The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide

Importance of zinc in the central nervous system: the zinc-containing neuron.

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