Aggregation of a-synuclein is a characteristic event in Parkinsons disease and other synucleinopathies that show age-dependent progression. The aggregated forms of the protein are associated with the presence of Lewy bodies and other pathological events. It is not certain if Lewy bodies, or a-synuclein aggregation per se, are required for the disease process. What is clear is that a-synuclein can be a toxic protein in several cellular and animal models, although the molecular details of these events are not well understood.
The aim of this project is to more clearly define what modifies a-synuclein aggregation and toxicity, and to try and understand why this is an age-related phenomenon. Several genetic risk factors for synucleinopathies, including variants around synuclein itself, have been identified. One well established risk factor are loss of function variants around the GBA locus which codes for glucocerebrosidase. Recessive GBA mutations cause Gauchers disease but also act as a risk factor for Parkinsons disease. In collaboration with Ellen Sidransky at NHGRI, we have shown that patients with GBA mutations have aggregated a-synuclein in the brain and that this correlates with Lewy pathology. In addition to other recent literature, this suggests that glucocerebrosidase likely has a strong effect on a-synuclein in cells and in the brain. This supports other work ongoing in the lab looking for genetic modifiers of a-synuclein using cell based models. In particular, we are developing new tools to look for genes that modify a-synuclein toxicity in cells that we hope eventually to apply to high throughput screening.
| 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
