title: Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury.
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.
authors.affiliation: NeuroRepair Group, Menzies Research Institute, University of Tasmania, Hobart, Tasmania 7001, Australia. rschung@utas.edu.au
authors.forename: Roger S
authors.initials: RS
authors.lastname: Chung
authors.forename: Milena
authors.initials: M
authors.lastname: Penkowa
authors.forename: Justin
authors.initials: J
authors.lastname: Dittmann
authors.forename: Carolyn E
authors.initials: CE
authors.lastname: King
authors.forename: Carole
authors.initials: C
authors.lastname: Bartlett
authors.forename: Johanne W
authors.initials: JW
authors.lastname: Asmussen
authors.forename: Juan
authors.initials: J
authors.lastname: Hidalgo
authors.forename: Javier
authors.initials: J
authors.lastname: Carrasco
authors.forename: Yee Kee J
authors.initials: YK
authors.lastname: Leung
authors.forename: Adam K
authors.initials: AK
authors.lastname: Walker
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Fung
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Dunlop
authors.forename: Melinda
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Lyn D
authors.initials: LD
authors.lastname: Beazley
authors.forename: Meng I
authors.initials: MI
authors.lastname: Chuah
authors.forename: James C
authors.initials: JC
authors.lastname: Vickers
authors.forename: Adrian K
authors.initials: AK
authors.lastname: West
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D001369:Axons / Q000378:metabolism* / Q000473:pathology; D001930:Brain Injuries / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D016166:Free Radical Scavengers / Q000493:pharmacokinetics / Q000494:pharmacology*; D008668:Metallothionein / Q000493:pharmacokinetics / Q000494:pharmacology*; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D012038:Regeneration / Q000187:drug effects*; D012165:Retinal Ganglion Cells / Q000378:metabolism* / Q000473:pathology
chemical_list: D016166:Free Radical Scavengers; D008668:Metallothionein