Parkinson's disease (PD) is the second most common neurodegenerative disease in humans. Pathologically, it is characterised by an accumulation of proteinaceous intraneuronal inclusions termed Lewy bodies (LBs). a-Synuclein is the major protein found at the core of LBs. However, it is not known what stimulus causes inclusion formation, or whether LBs are cytotoxic. I wished to address these questions using cell-based model systems. Consequently, stable transfected nonneuronal (HEK293) and neuronal (SH-SY5Y) cell lines were generated and cells could be induced to express wild type or mutants of a-synuc1ein. Moreover, the Parkin inducible cell lines were generated and used as a comparison. The characterisation of a-synuclein in HEK293 cells was demonstrated to have a relatively long half-life, and over-expression had no effect on cell death. In the absence of exogenous stimuli, over-expression of a-synuclein did not form inclusions. Only after the inhibition of proteasomal activity, inclusions were observed a relatively small number of cells. The mutated A53T form appeared to make the protein more prone to aggregate, and caused a greater level of cell· death. This data suggested that additional factors are required to provide an initial seed for inclusion formation in the presence of high concentrations of a-synuclein. A proteomic approach was then applied to determine if the over-expression asynuclein caused a wide-ranging effect on the cellular proteome. Few changes were observed. However, of particular interest, one of the most significant changes was a decreased level of the proteasome a7 subunit. Although this observation suggested that the levels of proteasomal activity may be altered in cells, I went on to demonstrate that over-expression of a-synuclein did not lead to an inhibition of total cellular proteasomal activity. One observation that may explain the long-term effect of a-synuclein in cells was that its over-expression caused the induction of the unfolded protein response followed by the activation of the endoplasmic reticulum-associated protein degradation (ERAD) pathway. Chronic activation of this pathway could induce apoptosis cells, eventually causing cell death.