Although α-synuclein plays a clear role in both the genetics and pathology of Parkinson disease, the mechanism by which α-synuclein causes neuronal cell death remains unknown. We have examined the effects of α-synuclein on the biology of cultured neuroblastoma cells and primary neurons. Overexpression of disease-causing forms of α-synuclein, including wild-type, can drive apoptosis and necrosis in cultured cells. These effects can be exaggerated by increasing the amounts of dopamine derived radicals in cells, suggesting that increased amounts of a-synuclein, especially mutant forms, sensitizes cells to cell death. Overexpression of wild-type α-synuclein also causes an increased susceptibility to mitochondrial complex I inhibition. We have begun analysis of a possible direct effect of α-synuclein on mitochondrial function by using live cell imaging of mitochondrial network integrity and are currently examining if mitochondrial complex I inhibition leads to more severe deficits in cells that overexpress α-synuclein. We will also use primary neurons from α-synuclein null mice as a model for testing the effect of α-synuclein variants on mitochondrial connectivity. A major advantage of this model is that it provides a more physiologic model that can be useful in extrapolating to the role of α-synuclein in vivo.? Aberrant post-translational modification of α-synuclein may also be a factor in the pathogenic mechanism of α-synuclein in Parkinsons disease. Phosphorylated α-synuclein (Ser129) is a major component of Lewy bodies and glial cytoplasmic inclusions and is therefore thought to play a critical pathogenic role in all synucleinopathies. In cases with a triplication of the a-synuclein gene, we have found that phosphorylated α-synuclein (Pser129-asyn) is disproportionately elevated in Lewy body containing brain regions suggesting this form of α-synuclein is at the very least a reliable marker of α-synuclein pathology. In cultured cells we have found that the detection of Pser129-asyn is directly correlated with the amount of total α-synuclein suggesting that overexpression of α-synuclein drives its phosphorylation. In future studies we will use primary neurons from SNCA null mice to examine how lack of Ser129 phosphorylation affects the turnover and possible aggregation of α-synuclein. In conjuction with mitochondrial network experiments mentioned above, we will also examine how phosphorylation at Ser129 affects α-synucleins cellular localization, one possibility being a phosphodependent interaction with mitochondria.
| Cookson, Mark R (2009) alpha-Synuclein and neuronal cell death. Mol Neurodegener 4:9 |
