Funded Studies
Study Rationale: Evidence suggests that alpha-synuclein causes the death of neurons in the brains of people with Parkinson’s disease (PD) by forming clusters (or ‘aggregates’) on the surface of membrane-bound structures inside the cell, including organelles and smaller vesicles. A number of chemical modifications of the alpha-synuclein protein have been identified in cellular and animal models of PD, as well as in the brains of people with PD. Little is known about how these modifications affect the ability of alpha-synuclein to form aggregates on organelle or vesicle surfaces in neurons.
Hypothesis: We hypothesize that certain chemical modifications of alpha-synuclein enhance its ability to form aggregates on the surface of organelles or vesicles in neurons, resulting in greater neuronal death or increased spread of aggregates in the brains of people with PD.
Study Design: Variants of alpha-synuclein that have been previously found in the brains of patients, including proteins with truncations and chemical phosphorylation, will be introduced into neurons and allowed to aggregate spontaneously or stimulated to form aggregates using a novel light-inducible clustering system. In both cases, we will observe closely how alpha-synuclein aggregates on the surface of different subcellular structures using fluorescence microscopy. We will also test the variants for their ability to induce the aggregation of the healthy, unmodified alpha-synuclein in neurons by a templating (or ‘seeding’) process.
Impact on Diagnosis/Treatment of Parkinson’s disease: By identifying modifications that enhance alpha-synuclein’s ability to form aggregates or to induce the clustering of healthy alpha-synuclein in neurons, we will learn more about how modified alpha-synucleins trigger neuronal loss and the spread of aggregates in PD, setting the stage for treatments to prevent these harmful alpha-synuclein modifications.
Next Steps for Development: The next steps toward clinical application of our findings will be to investigate whether the modifications identified in this project enhance the alpha-synuclein’s aggregation, spread and toxicity in preclinical animal models of PD and to screen for compounds that prevent harmful alpha-synuclein modification as potential PD therapies.