Specific Inhibition of Nucleation of Alpha-Synuclein Aggregation as a Therapeutic Strategy

The discovery of specific genes associated with rare, genetic forms of Parkinson’s disease has opened the opportunity to investigate the mechanisms of the disease and to develop novel drugs. Parkinson’s disease is typically characterized by abnormal protein aggregates called Lewy bodies in some neurons of the brain. The major component of these aggregates is a small protein called alpha-synuclein, and mutations in this protein, or genetic abnormalities that give rise to too much of it, cause inherited Parkinson’s disease. However, the precise role of alpha-synuclein in the pathogenesis of the most common, sporadic disease remains elusive, despite intensive investigations in laboratories around the world. Efforts to define the function of alpha-synuclein and to develop treatments based on our understanding that it is a crucial factor in the disease  have been hampered by the fact that this protein has been thought to exist as a random coil in vitro – an unfolded protein with about as much regular structure as a plate of cooked spaghetti. However, we hypothesized that alpha-synuclein?might actually adopt a folded structure in the cell, and we have now been able to prepare the protein in this state. Our goal is to characterize the structure and biochemical properties of this folded form of alpha-synuclein and determine its aggregation characteristics, both as the normal protein and as the mutants that are associated with the disease. Knowledge of the structure of the physiological form of alpha?synuclein will enable us to develop tests to detect it, which may be useful in early diagnosis. We also hope to find drugs to stabilize this structure and prevent it from converting into the form that is toxic to neurons. In addition, the protein that is found in aggregates consists of two forms:  a longer and a shorter form. An understanding of the process by which the smaller fragment is produced may allow us to develop compounds to prevent that cleavage, which we hypothesize is a crucial step in the aggregation of the protein.