Poor handling and elimination of misfolded proteins has been identified as central in the development of Parkinson’s disease (PD). A special class of proteins within the cell called “chaperones” can assist in improving protein handling. Our project will target a chaperone inhibitor called BAG5 that we know compromises protein handling and the function of other proteins important in PD. We hope to prove that inhibiting BAG5 — thereby allowing the chaperones to do their job — will be a novel treatment option for PD.
We will first develop specialized molecules that specifically bind to and inhibit BAG5 activity. As a second approach, we will develop custom molecules that prevent the production of BAG5 in cells using a technology called short-hairpin RNA (shRNA)-mediated knockdown. Following this we will “package” these custom molecular tools into virus-based delivery systems used for gene therapy. This approach will allow us to specifically inhibit BAG5 in the dopamine-producing brain cells in a pre-clinical models of PD.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Inhibiting or knocking down BAG5 is a potentially new way slow the course of PD by preventing the degeneration of dopamine-producing neurons in the brain.
If we can inhibit BAG5 activity, our findings will inform future investigation into different therapeutic strategies (gene therapy, novel drugs) that target BAG5 activity.