About This Project

Aggregation of misfolded alpha synuclein protein is a key feature of Parkinson's Disease (PD), which afflicts 53 million globally. There is no cure to PD to date and the current treatment, Levodopa, has changed little in the 60 years since introduced. Levodopa can result in side effects like dyskinesia. Chaperone proteins represent the cell's own response to misfolded proteins. This project intends to ID modifications to chaperone proteins to tailor them to target misfolded alpha synuclein.

Ask the Scientists

What is the context of this research?

Recent research on small chaperone proteins suggests the possibility of a molecular switch, which, if modified, would greatly increase the protein's effectiveness and specificity in targeting misfolded alpha-synuclein. We base our ideas on prior work with larger chaperone proteins, such as modifications to HSP104. This optimized chaperone will be chosen to have higher performance in refolding A-synuclein than the native, endogenous chaperone proteins.

( https://pdfs.semanticscholar.o... ).

What is the significance of this project?

Currently, 53 million people worldwide are afflicted with Parkinson's Disease. Treatments ranging from anticholinergic drugs to gene therapy targeting the LRRK2 gene have been tested; however there seems to be therapeutic promise in targeting the protein aggregation itself. Conventionally, this chaperoning was performed by small molecule kinetic stabilizers which mirror the actions of protein chaperones and have had a poor track record. The essence of this project is to use the chaperone proteins themselves, albeit in a potentiated (i.e. structurally modified) fashion. Small heat shock proteins are able to halt the PD advance. The use of proteins with similar structure and identical function as the native chaperones means treatment with fewer adverse side-effects and much reduced toxicity.

What are the goals of the project?

The experiments will show the feasibility of chaperone protein engineering as a viable Parkinson's therapeutic. It will also demonstrate the novel use of the small chaperone molecular switch to enhance alpha synuclein selectivity. We plan to publish our results in a peer-reviewed scientific journal.

First, I will do the in vitro testing of candidate proteins using Thioflavin T assays. This will be a confirmation of potentiated chaperoning activity.

Second, I will expand these tests into a cell culture model mimicking the cellular effects of PD. A lentiviral vector will insert a gene for the therapeutic protein for reduction of the aggregation phenotype.

Third, an in vivo Drosophila PD model will test the viability of this technique via a larval turning phenotype.