Tài liệu Báo cáo khoa học: Neuronal growth-inhibitory factor (metallothionein-3): evaluation of the

MINIREVIEW

Neuronal growth-inhibitory factor (metallothionein-3):

evaluation of the biological function of growth-inhibitory

factor in the injured and neurodegenerative brain

Claire Howells, Adrian K. West and Roger S. Chung

Menzies Research Institute, University of Tasmania, Hobart, Australia

Introduction

Metallothioneins (MTs) are a family of unusual cyste￾ine-rich (30%), 6–7 kDa proteins synthesized predomi￾nantly by astrocytes within the brain. The MT3 isoform

was first isolated and identified as a neuronal growth￾inhibitory factor (GIF) in 1991, a brain-specific protein

whose synthesis was notably deficient in the Alzheimer’s

disease (AD) brain. It was found to possess a strong

ability to impair neurite outgrowth and neuronal

survival of cultured neurons, leading to its designation

as GIF. It was later discovered that GIF shares approx￾imately 70% amino-acid sequence similarity with the

MT family of proteins, leading to its renaming as MT3.

Most striking is the conservation within GIF of the

unique cysteine motifs found in mammalian MTs.

Given that GIF shares a biochemical structure similar

to those of the other MT isoforms, it is not surprising

that GIF has the characteristic metal-binding and

reactive oxygen species (ROS) scavenging capabilities

present in all MT isoforms. However, GIF has also

been found to exhibit several unique biological proper￾ties, suggesting that this MT isoform has different and

distinct functions within the brain. Furthermore, the

discovery and continued investigation of this brain-spe￾cific MT isoform has led to intense interest in the roles

of the entire MT family in the brain, with particular

focus on the role of these proteins in the injured or

neurodegenerative brain.

Discovery of GIF

AD is a neurodegenerative disease that leads to severe

dementia and ultimately death. The pathological

hallmarks of the disease are intracellular neurofibril￾lary tangles, dystrophic neurites or curly fibres, and

Keywords

brain injury; metals; neuronal growth￾inhibitory factor (GIF); neurodegenerative

disease; oxidative stress

Correspondence

R. S. Chung, PhD, Private Bag 58,

University of Tasmania, Hobart, Tasmania

7001, Australia

Fax: +61 3 62262703

Tel: +61 3 62262657

E-mail: [email protected]

(Received 27 November 2009, revised

13 March 2010, accepted 19 May 2010)

doi:10.1111/j.1742-4658.2010.07718.x

Neuronal growth-inhibitory factor, later renamed metallothionein-3, is one

of four members of the mammalian metallothionein family. Metallothione￾ins are a family of ubiquitous, low-molecular-weight, cysteine-rich proteins.

Although neuronal growth-inhibitory factor shares metal-binding and reac￾tive oxygen species scavenging properties with the other metallothioneins,

it displays several distinct biological properties. In this review, we examine

the recent developments regarding the function of neuronal growth-inhibi￾tory factor within the brain, particularly in response to brain injury or

during neurodegenerative disease progression.

Abbreviations

AD, Alzheimer’s disease; Ab, b-amyloid; CNS, central nervous system; GIF, neuronal growth-inhibitory factor; KO, knockout;

MT, metallothionein; NO, nitric oxide; ROS, reactive oxygen species.

FEBS Journal 277 (2010) 2931–2939 ª 2010 The Authors Journal compilation ª 2010 FEBS 2931