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Alpha-, beta-, and gamma-synuclein: developmental localisation and response to cellular insult in neurons and oligodendrocytes

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Quilty, M (2009) Alpha-, beta-, and gamma-synuclein: developmental localisation and response to cellular insult in neurons and oligodendrocytes. PhD thesis, University of Tasmania.

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Abstract

Alpha-synuclein is a highly conserved, ubiquitously expressed protein in the
vertebrate brain. It was discovered in 1988 and was purported to play a role in song
learning, implicating a role in synaptic plasticity. Alpha-synuclein came under
increased scrutiny shortly thereafter as the non-amyloid component isolated from
plaques from Alzheimer’s disease brains. Following this discovery, alpha-synuclein
was further characterised as the main component in numerous additional inclusion
bodies found in several neurodegenerative disease leading to speculation that alphasynuclein
was involved in disease pathogenesis.
Two decades later little is known about the normal function of alpha-synuclein in
neuronal cells, however numerous studies have determined alpha-synuclein is able to
form fibrils and aggregates, and that these may provide the neurotoxic mechanism by
which alpha-synuclein exerts its effect in disease states. Other studies have
demonstrated the formation of fibrillar aggregates of alpha-synuclein is a
neuroprotective mechanism. The issues of the cellular role and neurotoxicity of
alpha-synuclein remain contentious. This thesis provides evidence indicating a
developmentally regulated role for alpha-synuclein in neurons and oligodendrocytes,
as well as roles in neuroprotection, plasticity and regeneration. This thesis has
demonstrated synuclein isoforms have a distinct pattern of localisation during
neuronal development, indicating alpha-, beta- and gamma-synuclein also have
distinct functionality within neuronal development, and that these functions may
alter as neurons develop.
Alpha-synuclein immunoreactive neuritic abnormalities were shown to be caused by
physical insult to the axon, leading to the accumulation of alpha-synuclein protein in
neuronal processes, and were associated with neurofilament pathology mirroring that
seen in some disease states containing aggregated forms of alpha-synuclein. It was
demonstrated alpha-synuclein is involved in regenerative sprouting following axonal
injury, further implying a role for alpha-synuclein in aspects of growth cone
development and/or maturation as well as neuronal plasticity.
Additionally, synuclein isoforms were shown to have a distinct pattern of localisation
during oligodendroglial development, indicating alpha-, beta- and gamma-synuclein
also have distinct functionality within oligodendrocytes, and these functions may
alter throughout development. In this case exogenous alpha-synuclein was
demonstrated to be taken up by oligodendrocytes, and incorporated into cytoplasmic
inclusions, along with endogenous alpha-synuclein, implying a mechanism by which
alpha-synuclein interacts with oligodendrocytes in disease states leading to the
formation of glial cytoplasmic inclusions. Finally, and importantly this thesis
demonstrated an increase in alpha-synuclein in response to stressful stimuli is
beneficial to neuronal survival as part of a normal neuronal response in a
subpopulation of neurons. This finding is somewhat contentious as many of the
studies into the role and mechanism of alpha-synuclein in disease states support its
neurotoxicity, yet this thesis contradicts this, providing evidence for a
neuroprotective affect of alpha-synuclein.

Item Type: Thesis (PhD)
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Date Deposited: 28 Apr 2011 05:09
Last Modified: 11 Mar 2016 05:53
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