One approach to understanding the toxicity of alpha-synuclein in Parkinson’s disease arose from our finding that while the mouse form of the protein is very similar to the human alpha-synuclein, the mouse form of the protein protects against the toxicity of human alpha-synuclein. We have generated toxic variants of the mouse protein and are assessing differences in properties between the wild type and toxic mouse alpha-synucleins.
Mouse alpha-synuclein variants differ in their toxicity in yeast. Variants were cloned in a galactose-inducible expression vector, and identical dilution series were spotted on glucose and galactose plates. No alpha-synuclein is produced on glucose plates (left). On the galactose plates (right), alpha-synuclein is expressed, and toxic forms of the mouse protein inhibit or prevent growth of the yeast (left panel, bottom half).