PDF (Whole thesis) whole_FungSaman...pdf | Request a copy Full text restricted Available under University of Tasmania Standard License.

Abstract

The primary function of metallothioneins (MTs) remains elusive since their
discovery 50 years ago. These small proteins are characterised by their metal-binding
capability, implying roles in metal ion homeostasis and free radical
scavenging. This study focuses on MT in the central nervous system (CNS), where
MT-I and -II are the topic of much recent research into their activity in promoting
neurite growth and enhancing wound healing in various in vivo and in vitro models.
This thesis aims to investigate the interaction of extracellular MT-I/II with neurons
and the molecular mechanism through which it impacts neurite outgrowth. The
physiological role of MT-I/II in CNS development will also be examined.
Within the CNS, MT-I/II expression is primarily non-neuronal, yet MT-I/II alters the
growth of neurons, suggesting an extracellular action. In order to investigate the
mechanism by which extracellular MT-I/II interacts with neurons, rat cortical
neurons were exposed to substrate-bound or soluble exogenous MT-IA. An
increase in process length was noted only in the presence of soluble exogenous MT-IIA,
suggesting that a specific interaction of MT-I/II and neurons is required for
neurotrophic activity. Indeed, extracellular MT-I/II was internalised by neurons,
mediated by an interaction with the endocytic receptor megalin. Moreover, MT-I/II
treatment resulted in activation of the MAPK/ERK signalling pathway, providing a
downstream target of MT-I/II. When MT-I/II was ectopically expressed in neurons,
neurite outgrowth was augmented, implying an intracellular action.
Further, the effect of exogenous MT-IIA on a population of growing, immature
cortical neurons was examined. Neurite growth was not observed in this model of
neurite elongation in contrast to that seen in neurite outgrowth models and possible
reasons for this were addressed.
Finally, MT-I/II null mice display no major phenotype; however subtle alterations in
cognitive function and axonal structure have recently been reported. Within this
study a reduction in axonal calibre at one month of age was observed in mice lacking
MT-I/II genes. Moreover, the expression and phosphorylation of neurofilaments was delayed in MT-I/II null mice, suggesting that MT-I/II may contribute to normal
axonal development.
In summary, this thesis provides some insight into the possible molecular
mechanisms through which extracellular MT-I/II interacts with neurons to promote
neurite growth and suggests that MT-I/II expression contributes to the normal
development of axons. Understanding of the physiology of MT-I/II and mechanisms
through which it operates may contribute to development of MT-I/II-based
therapeutics applicable to CNS injury and neurodegenerative diseases.

Item Type:	Thesis - PhD
Authors/Creators:	Fung, Samantha Jane
Keywords:	Metallothionein, Neurons, Central nervous system
Copyright Holders:	The Author
Copyright Information:	Copyright 2008 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:	Thesis (PhD)--University of Tasmania, 2008. Includes bibliographical references
Item Statistics:	View statistics for this item

Actions (login required)

Item Control Page