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

TY - JOUR

T1 - Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury

AU - Chung, Roger S

AU - Penkowa, Milena

AU - Dittmann, Justin

AU - King, Carolyn E

AU - Bartlett, Carole

AU - Asmussen, Johanne W

AU - Hidalgo, Juan

AU - Carrasco, Javier

AU - Leung, Yee Kee J

AU - Walker, Adam K

AU - Fung, Samantha J

AU - Dunlop, Sarah A

AU - Fitzgerald, Melinda

AU - Beazley, Lyn D

AU - Chuah, Meng I

AU - Vickers, James C

AU - West, Adrian K

N1 - Keywords: Animals; Astrocytes; Axons; Brain Injuries; Cells, Cultured; Free Radical Scavengers; Metallothionein; Optic Nerve; Protein Transport; Rats; Regeneration; Retinal Ganglion Cells

PY - 2008

Y1 - 2008

N2 - 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.

AB - 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.

U2 - 10.1074/jbc.M708446200

DO - 10.1074/jbc.M708446200

M3 - Journal article

C2 - 18334482

SN - 0021-9258

VL - 283

SP - 15349

EP - 15358

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

IS - 22

ER -