Several lines of evidence support the idea that alpha-synuclein plays a key role in both inherited and sporadic Parkinsons disease. First, mutations in the a-synuclein gene, including multiplication variants, are causative for PD or similar diseases. Second, common genetic variants around the a-synuclein locus alter lifetime risk of sporadic PD. Third, the a-synuclein protein is a major component of Lewy bodies, the characteristic pathological inclusion found in PD. However, understanding why a-synuclein is associated with characteristic patterns of neuronal cell death is unclear. In the current period, we have been involved in two studies trying to understand why a-synuclein might be toxic and how this might be prevented. In the first, we have shown that a-synuclein in its putatively toxic oligomeric form can limit the efficiency of lysosomal clearance of proteins in the cell. This may be related to the observation that a lysosomal enzyme, glucocerebrosidase, is associated genetically associated with risk of PD. In the second, we were able to show that farnesyl transferase inhibitors can limit a-synuclein toxicity in cell culture models. This may be related to inhibition of another protein turnover enzyme, ubiquitin-C terminal hydrolase 1 (UCHL1). However, the fundamental question of how a-synuclein kills neurons is still unclear as a direct molecular target remains to be identified. Therefore, future work will be directed at developing large scale screening methods to address these problems.
| Bandres-Ciga, Sara; Cookson, Mark R (2017) Alpha-synuclein triggers T-cell response. Is Parkinson's disease an autoimmune disorder? Mov Disord 32:1327 |
| Wang, Wei; Nguyen, Linh T T; Burlak, Christopher et al. (2016) Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein ?-synuclein. Proc Natl Acad Sci U S A 113:9587-92 |
| Kumaran, Ravindran; Cookson, Mark R (2015) Pathways to Parkinsonism Redux: convergent pathobiological mechanisms in genetics of Parkinson's disease. Hum Mol Genet : |
| Cookson, Mark R (2014) Lardy brains make Parkinson's disease mice worse. J Neurochem 131:697-8 |
| Dehay, Benjamin; Martinez-Vicente, Marta; Caldwell, Guy A et al. (2013) Lysosomal impairment in Parkinson's disease. Mov Disord 28:725-32 |
| Choi, Jae Hyuk; Stubblefield, Barbara; Cookson, Mark R et al. (2011) Aggregation of ?-synuclein in brain samples from subjects with glucocerebrosidase mutations. Mol Genet Metab 104:185-8 |
| Cookson, Mark R (2011) A feedforward loop links Gaucher and Parkinson's diseases? Cell 146:9-11 |
| Wang, Wei; Perovic, Iva; Chittuluru, Johnathan et al. (2011) A soluble ?-synuclein construct forms a dynamic tetramer. Proc Natl Acad Sci U S A 108:17797-802 |
| Bisaglia, Marco; Greggio, Elisa; Maric, Dragan et al. (2010) Alpha-synuclein overexpression increases dopamine toxicity in BE2-M17 cells. BMC Neurosci 11:41 |
| Cookson, Mark R (2009) alpha-Synuclein and neuronal cell death. Mol Neurodegener 4:9 |
Showing the most recent 10 out of 13 publications
