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

There is considerable evidence that aggregates of the human brain protein alpha-synuclein are a primary cause of the loss of neurons in Parkinson's disease.  We have tried to find out what initiates this aggregation so that it can be prevented. 

Using a novel model system involving human synuclein expressed in the same type of yeast that is used to make beer, bread or wine, we have found that synuclein is cut in a specific place and that the resulting fragments seem to be associated with the start of aggregation.  We have identified two protein-cutting enzymes in yeast that make these fragments, and shown that deleting them or inhibiting them with drugs is enough to prevent human synuclein from killing a yeast cell. 

Since the same fragments are found in the Lewy bodies in Parkinson's patients, and since the same protein-cutting enzymes are found in human brain cells, we believe that inhibiting these enzymes represents a promising strategy for protecting neurons against synuclein toxicity.  However, there are many different forms of these enzymes in human cells, so the goal of our project now is to identify which one(s) of them are carrying out the same function in the brain as their relatives did in yeast. 

Once we have narrowed down the target hunt to the specific enzymes responsible for the fragmentation in neurons, we will make specific inhibitors of these enzymes and then test them in animal models of Parkinson's disease.