Several laboratories using different model systems have approached understanding why alpha-synuclein is toxic to cells. Our approach has been to develop a mammalian system where we can induce alpha-synuclein protein over several days with the long term goal of then finding genes that can block the effect. In parallel, we made cell lines expressing tau. Despite several previous publications supporting an acute toxic effect, we have fairly modest toxicity in our model. We are therefore addressing different strategies to recover modifiers. These include testing genes that are reported to worsen alpha-synuclein toxicity from previous papers, trying different measures of toxicity, and increasing the length of time for which toxic proteins are expressed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000939-06
Application #
8736655
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2013
Total Cost
$422,418
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Wang, Wei; Nguyen, Linh T T; Burlak, Christopher et al. (2016) Caspase-1 causes truncation and aggregation of the Parkinson's disease-associated protein α-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 α-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 α-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
Yu, Wai Haung; Dorado, Beatriz; Figueroa, Helen Yvette et al. (2009) Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein. Am J Pathol 175:736-47

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