Study Rationale:
For cells to operate properly, the proteins they produce must fold properly and maintain the correct three-dimensional structure. This process relies on a special class of proteins, termed molecular chaperones, that assist and safeguard the proper folding of proteins in the cell. As we age, the chaperone capacity in the cell decreases, leading to the misfolding and aggregation of proteins that can damage cells and precipitate disease. Parkinson’s disease (PD) is an example of a disease that is rooted in the toxic aggregation of the protein alpha-synuclein.
Hypothesis:
In this project, we will test the idea that a new class of chaperones, dubbed tailor-made molecular chaperones (TMMCs), can be evolved to recognize alpha-synuclein and keep it from misfolding and forming toxic aggregates.
Study Design:
To produce TMMCs, we will leverage the power of directed evolution, an experimental process in which collections of 10,000 to 10 million chaperones bearing small differences from one another are iteratively generated and tested for their ability to recognize and protect sequences on alpha-synuclein. The TMMCs that are the most effective will provide a growth advantage to the cells that contain them.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
We hope that TMMCs evolved to preserve normal alpha-synuclein structure can be used to supplement the reduced chaperone capacity in aging cells, protecting them from the toxicity caused by alpha-synuclein aggregation.
Next Steps for Development:
After the evolved TMMCs have been shown to protect neuronal cell models from alpha-synuclein aggregation, we hope to extend the testing of their efficacy in pre-clinical models of PD.