Lake Forest College, Biology, Northbrook, IL 60062
Parkinson’s disease is a devastating and incurable neurodegenerative disorder that afflicts over one million Americans. A universal symptom of the disease is the presence of protein aggregates located in substantia nigra neurons. In Parkinson’s, these neurons ultimately die, but the role that the aggregates play in their death is unclear. Debate rages about whether these aggregates are neuroprotective or harmful to the cell. The chief component of these clusters is the protein alpha-synuclein. This protein has high affinity for binding phospholipids, but how that contributes to function or disease is unclear. Previously, scientists mathematically modeled alpha-synuclein and suggested that the 76th amino acid (alanine) might be a key factor mediating its propensity to aggregate and also bind phospholipids. We specifically tested this hypothesis by mutating this alanine to glutamic acid (A76E), and asked if A76E alpha-synuclein was less able to aggregate and/or bind phospholipids in live cells. In support of this hypothesis, using a budding yeast model, we found that less A76E alpha-synuclein was bound to the plasma membrane. Furthermore, using a fission yeast model, we found that less A76E alpha-synuclein was aggregated. In both cases, more alpha-synuclein was found cytoplasmically diffuse. To our surprise, in neither model system did A76E alpha-synuclein significantly induce or reduce toxicity, suggesting that yeast are particularly adept at protecting against alpha-synuclein’s toxic properties.
M.F. was supported by the Lake Forest College Richter Scholar Program and by an NIH R15 AREA grant to S.D.