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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

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Chung, RS and Penkowa, M and Dittman, J and King, CE and Bartlett, C and Asmussen, JW and Hidalgo, J and Carrasco, J and Leung, YK and Walker, AK and Fung, SJ and Dunlop, SA and Fitzgerald, M and Beazley, LD and Chuah, MI and Vickers, JC and West, AK (2008) Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. Journal of Biological Chemistry, 283 (22). pp. 15349-15358. ISSN 0021-9258

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Abstract

Anumber 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,
wehave previously established that astrocyticMTsare 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,weidentify a receptor, megalin, that mediatesMTtransportintoneurons.
Third,wedirectlydemonstratefor
the first time the transfer ofMTfrom astrocytes to neurons over a
specific time course in vitro. Finally, we show that MT is rapidly
internalizedviathecellbodiesofretinalganglioncellsinvivoandis
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
nervoussystemshouldbewidenedfromapurelyastrocyticfocusto
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

Item Type: Article
Journal or Publication Title: Journal of Biological Chemistry
Page Range: pp. 15349-15358
ISSN: 0021-9258
Identification Number - DOI: 10.1074/jbc.M708446200
Additional Information:

Copyright © 2008 by the American Society for Biochemistry and Molecular Biology.

Date Deposited: 02 Jul 2008 22:31
Last Modified: 18 Nov 2014 03:44
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