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The role of extracellular metallothioneins in the cellular response to neuronal injury


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Chung, Roger Steven 2003 , 'The role of extracellular metallothioneins in the cellular response to neuronal injury', PhD thesis, University of Tasmania.

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Metallothioneins (MTs) are unusual, cysteine rich proteins, which can
sequester heavy metals (including zinc and cadmium), and also have free radical
scavenging properties, which allow them to protect cells from cytotoxicity
induced by reactive oxygen species. In the last 10 years, interest in the potential
roles of these proteins has shifted from metal homeostasis and free radical
scavenging to the neurological functions which they may possess. In this regard,
it is the brain specific, MT-III isoform, which has been of most interest. This
protein exhibits neuronal growth inhibitory properties upon cultured cortical
neurons, and also has been proposed to be involved in the development of
Alzheimer's disease. The aim of this thesis is to further investigate the proposed
neuroactive properties of MTs, at both a functional and biological level, to
determine their possible role within the brain.
This study firstly investigated the relationship between structure and
biological function of MT-III by investigating the neuronal growth inhibitory
activity of a variant MT-III protein previously identified in this laboratory,
namely sheep MT-III. This protein was produced recombinantly, and by
comparison with recombinant human MT-III, reductions in its metal binding and
neuronal growth inhibitory activity upon cultured cortical rat neurons were found.
These results indicate the importance of protein structure to MT-III's inhibitory
activity, and may also partly explain the susceptibility of sheep to heavy metal
induced toxicity.
MT-III has. also been proposed to inhibit neurite outgrowth, although all
available studies in the literature have alternatively focused upon its ability to
inhibit neuronal survival. Using recombinant human MT-III, this study found that
MT-III does indeed inhibit initial neurite formation and growth when applied to
cultured cortical rat neurons. Furthermore, following axonal transection in
culture, MT-III inhibited reactive (or regenerative) neurite sprouting. These
results support the hypothesis in the literature that reduced levels of MT-III in the
brain allow the aberrant neurite sprouting observed in Alzheimer's disease.
Rather surprisingly, it was found that another MT isoform, human MTIA,
promoted neurite elongation, reactive sprouting, and growth following injury
in the same culture models. At the same time, several reports in the literature
demonstrated that MT-I and —II knockout mice had significantly reduced cortical
wound healing capacity and that exogenous application of MT-II promoted
cortical wound healing. To elucidate whether the neuroactive properties observed
in culture within this study were involved in this response, human MT-IA was
applied following focal cortical brain injury in the adult rat. MT-IIA promoted
marked neural recovery following injury, suggesting that MT-I and MT-II might
act in an extracellular capacity to promote cortical wound healing, as well as their
better investigated intracellular roles.
Based upon the demonstration, both within the literature and this thesis,
that MTs can modulate neural recovery following injury, it was hypothesized that
these properties might relate to their physiological function within the brain. In
this regard, this hypothesis would explain the observation within the literature that
MT-I and —II are up-regulated within astrocytes in response to various forms of
brain injury and neurodegenerative disorders. Using neuron/astrocyte co-cultures,
this study found a similar pattern of MT-I and —II up-regulation following scratch
wound injury. However, injury to pure astrocyte cultures did not result in
changes in MT-I and —II expression, suggesting that MT-I and —II respond
specifically to neuronal injury. Based upon these results, .this thesis proposes a
potential model/hypothesis for MT action within the CNS, where they are upregulated
in astrocytes in response to neuronal injury, released, and subsequently
promote/inhibit neuronal recovery.
In summary, this thesis presents data suggesting an important role for
extracellular MTs in the cellular response to neuronal injury. Furthermore, the
neuroactive properties of MTs discovered in this work reveal the possibility of
metallothionein based therapeutics in the context of brain injury.

Item Type: Thesis - PhD
Authors/Creators:Chung, Roger Steven
Keywords: Neurons, Metallothionein, Neurons, Nervous system
Copyright Holders: The Author
Copyright Information:

Copyright 2003 the Author - The University is continuing to endeavour to trace the copyright
owner(s) and in the meantime this item has been reproduced here in good faith. We
would be pleased to hear from the copyright owner(s).

Additional Information:

For consultation only. No loan or photocopying permitted until 22 August 2005. Thesis (Ph.D.)--University of Tasmania, 2003. Includes bibliographical references

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