Cell systems and the toxic mechanism(s) of alpha-synuclein

Mutations in the SNCA gene are causal for familial Parkinson disease/Lewy body disease. alpha-Synuclein is a small acidic protein that binds loosely to the surface of vesicles and may play a role in synaptic dynamics, although its normal function remains somewhat unclear. What is clear is that point mutations or increased expression of wild type alpha-synuclein causes disease. A great deal of literature supports the overall hypothesis that alpha-synuclein is damaging to neurons because it is inherently prone to aggregation; mutations or increased concentration of the protein both increase this tendency. An unproven, but popular, contention is that the toxic species are small oligomers that are relatively soluble, which may react with membranes to damage key processes within the cell. The details of this process, especially in determining the order of events and the requirement of particular processes in cell death, are unclear. Derangements in vesicle processing, including synaptic function, protein turnover, mitochondrial function and oxidative stress, have all been suggested to occur. Whether there is a sequence of events or whether these are interacting effects is unclear, but the outcome is to trigger cell death, by both apoptotic and non-apoptotic mechanisms depending on the system studied. In this article, we develop a framework for thinking about alpha-synuclein in terms of initiating events and secondary processes that are required to trigger neuronal dysfunction and cell death.