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Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury

journal contribution
posted on 2023-05-16, 21:51 authored by Chung, RS, Penkowa, M, Dittmann, J, Carolyn KingCarolyn King, Bartlett, C, Asmussen, JW, Hidalgo, J, Carrasco, J, Jacqueline LeungJacqueline Leung, Walker, AK, Fung, SJ, Dunlop, SA, Fitzgerald, M, Beazley, LD, Meng Inn ChuahMeng Inn Chuah, James VickersJames Vickers, Adrian WestAdrian West
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 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.

Funding

Australian Research Council

History

Publication title

Journal of Biological Chemistry

Volume

283

Issue

22

Pagination

15349-15358

ISSN

0021-9258

Department/School

Menzies Institute for Medical Research

Publisher

American Society for Biochemistry and Molecular Biology, Inc.

Place of publication

USA

Rights statement

Copyright 2008 The American Society for Biochemistry and Molecular Biology, Inc.

Repository Status

  • Restricted

Socio-economic Objectives

Clinical health not elsewhere classified

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