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Latest in Metallothionein Research

Updated: November 10, 2008

 

Redefining the Role of Metallothionein within the Injured Brain
EXTRACELLULAR METALLOTHIONEINS PLAY AN IMPORTANT ROLE IN THE ASTROCYTE-NEURON RESPONSE TO INJURY.

Roger S. Chung1, Milena Penkowa2, Justin Dittmann1, Carolyn E. King
3, Carole Bartlett3, Johanne W. Asmussen2, Juan Hidalgo4, Javier Carrasco4, Yee Kee J. Leung1, Adam K. Walker1, Samantha J. Fung1, Sarah A. Dunlop3, Melinda Fitzgerald3, Lyn D. Beazley3, Meng I. Chuah1, James C. Vickers1, and Adrian K. West1


1NeuroRepair Group, Menzies Research Institute, University of Tasmania, Private Bag 58, Hobart, Tasmania 7001, Australia,

2Section of Neuroprotection, Faculty of Health Sciences, University of Copenhagen, Copenhagen DK2200, Denmark,

3School of Animal Biology, University of Western Australia, Nedlands, Western Australia 6907, Australia, and

4Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Bellaterra, Barcelona 08193, Spain


Journal of Biological Chemistry, Vol. 283, Issue 22, 15349-15358, May 30, 2008.

Abstract: A number of intracellular proteins that are protective after brain injury are classically thought to exert their effect within the expressing cell. The astrocytic metallothioneins (MT) are one example and are thought to act via intracellular free radical scavenging and heavy metal regulation, and in particular zinc. Indeed, we have previously established that astrocytic MTs are required for successful brain healing. Here we provide evidence for a fundamentally different mode of action relying upon intercellular transfer from astrocytes to neurons, which in turn leads to uptake-dependent axonal regeneration. First, we show that MT can be detected within the extracellular fluid of the injured brain, and that cultured astrocytes are capable of actively secreting MT in a regulatable manner. Second, we identify a receptor, megalin, that mediates MT transport into neurons. Third, we directly demonstrate for the first time the transfer of MT from astrocytes to neurons over a specific time course in vitro. Finally, we show that MT is rapidly internalized via the cell bodies of retinal ganglion cells in vivo and is a powerful promoter of axonal regeneration through the inhibitory environment of the completely severed mature optic nerve. Our work suggests that the protective functions of MT in the central nervous system should be widened from a purely astrocytic focus to include extracellular and intra-neuronal roles. This unsuspected action of MT represents a novel paradigm of astrocyte-neuronal interaction after injury and may have implications for the development of MT-based therapeutic agents.
 

 

New insight into the molecular pathways of metallothionein-mediated neuroprotection and regeneration

R. S. Chung*, J. Hidalgo† and A. K. West*

*NeuroRepair Group, Menzies Research Institute, University of Tasmania, Hobart, Tasmania, Australia
†Institute of Neurosciences and Department of Cellular Biology, Physiology and Immunology, Animal Physiology Unit, Faculty of Sciences, Autonomous University of Barcelona, Bellaterra, Barcelona, Spain
Address correspondence and reprint requests to R. S. Chung, NeuroRepair Group, Menzies Research Institute, University of Tasmania, Private Bag 58, Hobart, Tasmania Australia 7001.
E-mail: rschung@utas.edu.au

Keywords: MAG, myelin-associated glycoprotein; MT, metallothionein; LDL, low density lipoprotein; CREB, cAMP response element binding protein.

Abstract

There is a large body of evidence demonstrating that metallothioneins (MTs) expressed in astrocytes following CNS injury, exhibit both neuroprotective and neuroregenerative properties and are critical for recovery outcomes. As these proteins lack signal peptides, and have well characterized free radical scavenging and heavy metal binding properties, the neuroprotective functions of MTs have been attributed to these intracellular roles. However, there is an increasing realization that the neuroprotective functions of MTs may also involve an extracellular component. In this issue of Journal of Neurochemistry, Ambjørn et al. reveal considerable insight into this novel function of MTs. In this review, we examine the seminal work of Ambjørn et al. in the context of our current understanding of the role of MT in astrocyte-neuron interactions in the injured brain, and also discuss the significant therapeutic potential of their work.

Full article here   PDF   Journal of Neurochemistry

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Metallothionein and a peptide modeled after metallothionein, EmtinB, induce neuronal differentiation and survival through binding to receptors of the low-density lipoprotein receptor family.

Malene Ambjørn*, Johanne W. Asmussen*,†, Mats Lindstam*, Kamil Gotfryd*, Christian Jacobsen‡, Vladislav V. Kiselyov*, Søren K. Moestrup‡, Milena Penkowa†, Elisabeth Bock* and Vladimir Berezin*

*Protein Laboratory, Institute of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark
†Section of Neuroprotection, Institute of Neuroscience and Pharmacology, University of Copenhagen, Copenhagen, Denmark
‡Institute of Medical Biochemistry, University of Aarhus, Aarhus, Denmark
Address correspondence and reprint requests to Vladimir Berezin, Protein Laboratory, Institute of Neuroscience and Pharmacology, University of Copenhagen, Panum Institute Building 6.2, Blegdamsvej 3, DK-2200 Copenhagen N, Denmark. E-mail: berezin@plab.ku.dk

Keywords: 7DIV, 7 days in vitro; Bcl-2, B-cell leukemia/lymphoma-2; BH, Bcl-2 homology; BimS, Bcl-2 interacting member of cell death, short isoform; BSA, bovine serum albumin; CGN, cerebellar granule neuron; CREB, cAMP response element binding protein; ERK, extracellular signal-regulated kinase; LDLR, low-density lipoprotein receptor; LRP, low-density lipoprotein receptor-related protein; MT, metallothionein; NB-A, neurobasal-A; PACE, phosphospecific antibody cell-based ELISA; PBS, phosphate-buffered saline; PKB/Akt, protein kinase B; RAP, receptor-associated protein-1.


Abstract

Accumulating evidence suggests that metallothionein (MT)-I and -II promote neuronal survival and regeneration in vivo. The present study investigated the molecular mechanisms underlying the differentiation and survival-promoting effects of MT and a peptide modeled after MT, EmtinB. Both MT and EmtinB directly stimulated neurite outgrowth and promoted survival in vitro using primary cultures of cerebellar granule neurons. In addition, expression and surface localization of megalin, a known MT receptor, and the related lipoprotein receptor-related protein-1 (LRP) are demonstrated in cerebellar granule neurons. By means of surface plasmon resonance MT and EmtinB were found to bind to both megalin and LRP. The bindings were abrogated in the presence of receptor-associated protein-1, an antagonist of the low-density lipoprotein receptor family, which also inhibited MT- and EmtinB-induced neurite outgrowth and survival. MT-mediated neurite outgrowth was furthermore inhibited by an anti-megalin serum. EmtinB-mediated inhibition of apoptosis occurred without a reduction of caspase-3 activity, but was associated with reduced expression of the pro-apoptotic B-cell leukemia/lymphoma-2 interacting member of cell death (BimS). Finally, evidence is provided that MT and EmtinB activate extracellular signal-regulated kinase, protein kinase B, and cAMP response element binding protein. Altogether, these results strongly suggest that MT and EmtinB induce their neuronal effects through direct binding to surface receptors belonging to the low-density lipoprotein receptor family, such as megalin and LRP, thereby activating signal transduction pathways resulting in neurite outgrowth and survival.

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