α-synuclein is an abundant and conserved presynaptic brain protein (Uversky 2007). It has received extensive attention since its aggregation was identified as the main component of Lewy bodies and Lewy neurites, which is the pathological hallmark of several neurodegenerative diseases, collectively known as synucleinopathies, including Parkinson's Disease (PD) (Uversky 2007). Considerable information has been collected about the structural properties and conformational behavior of α-synuclein, although the precise function is still under investigation. Metal ions such as copper and iron, can accelerate the aggregation and fibrillation of α-synuclein. Metal ions may exert their dual physiopathological properties through the interaction with α-synuclein, converting protein structure and/or inducing oxidative stress. In this study, isothermal titration calorimetry and electron paramagnetic resonance were used to determine the metal-binding property of the synuclein proteins, proving the presence of four Cu(II) binding sites per molecular of α-synuclein, with the coordination modes of 1N3O and 2N2O. Furthermore, α-synuclein has a catalytic action on the redox cycling of Cu(II), which was assessed by the application of cyclic voltammetry. However, this property is absent on β-synuclein and γ-synuclein, which belong to the synuclein family and have been suggested to be the physiological regulators of α-synuclein expression. In vivo, immunofluoresence studies revealed that Cu(II) increases the aggregates formation in mammalian doperminergic neuron cells overexpressing α-synuclein and the PD-associated mutants, while no aggregates have been found in cells overexpressing β-synuclein and γ-synuclein.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:512329 |
| Date | January 2009 |
| Creators | Wang, Xiaoyan |
| Contributors | Brown, David |
| Publisher | University of Bath |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
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