The pathological hallmark of Parkinson's disease is the accumulation in nerve cells of dense clumps of aggregated protein. The clumps, called Lewy bodies, contain mostly a protein called alpha-synuclein, which does not normally form such aggregates in healthy brain cells.
Although a lot of Parkinson's research is currently focused on trying to break up these aggregates before they can cause cell death, we decided on a different approach: to prevent them from forming in the first place. We wondered what might be nucleating the formation of the synuclein aggregates, so we extracted the aggregated material and analyzed it for something that could seed the process. We found smaller fragments of synuclein, which were only present in the aggregates, not in the soluble form of the protein. In the test tube, these fragments seem to aggregate much more readily than the full-length protein. Since the fragments are specific, they must be the product of the clipping of synuclein by a specific digestive enzyme in the neuron.
The aim of our project is to identify this enzyme, using a powerful genetic model system, with the longer-term goal of seeing if inhibiting the enzyme with a specific drug might block the formation of the synuclein fragments and thus prevent or delay the formation of the aggregates that these fragments promote. Inhibiting an enzyme is much easier than breaking up a clump of protein (many known drugs are enzyme inhibitors), so if we succeed in identifying the likely enzyme, we should have a good target for a novel form of Parkinson's disease therapy.
Dr. Petsko used a yeast model engineered to express human alpha-synuclein and identified several proteases that cleave alpha-synuclein. He subsequently received supplemental funding to move into mammalian cells to determine whether the same proteases identified in yeast were capable of cleaving alpha-synuclein and enhancing toxicity. Identification of specific proteases that could serve as targets would allow Dr. Petsko to initiate a drug development program for compounds that can inhibit these enzymes.