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

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.