Small-Molecule Pharmacological Chaperones Reverse Alpha-synuclein-impaired Debris Removal
Therapeutic Pipeline Program, 2017
The goal of this project is to find therapeutic drugs for Parkinson's disease (PD) that target alpha-synuclein, a key player in PD. We propose that the negative impact of alpha-synuclein on called vesicles (storage packets) and the block of cell functions, including debris removal (phagocytosis) and nerve signaling, leads to disease progression. We are developing therapeutic compounds to reverse this effect.
Using a novel approach, we previously identified compounds that reverse the adverse effect of alpha-synuclein on vesicle function, leading to a reversal of alpha-synuclein-impaired debris removal. We aim to improve these compounds as a critical next step in developing therapeutic drugs based on this approach.
We will test our compounds for potency and for their ability to work in the right type of cells that clear debris in the brain (microglial cells). We aim to demonstrate a specific impact on alpha-synuclein by showing that our compounds do not affect normal cellular debris removal or debris removal in the absence of alpha-synuclein. We will also test the ability of these compounds to reverse alpha-synuclein impairment on nerve signaling. The ideal compounds would reverse alpha-synuclein impairment of both debris removal and nerve signaling. Finally, we will test the most promising compounds in pre-clinical models.
Impact on Diagnosis/Treatment of Parkinson's disease:
The compounds we develop in these studies will be used as leads to develop drugs that can slow the progression of PD.
Next Steps for Development:
The compounds we identify will next be tested for beneficial impact in PD models to prevent disease-relevant neuron degeneration and alpha-synuclein aggregation (clumping). These studies will provide validation for our hypothesis that reversal of alpha-synuclein-impaired debris removal and nerve signaling is disease-relevant and will pave the way toward optimization of these leads as therapies for PD.
Professor at The University of California, San Francisco
Location: San Francisco, California, United States