Promising Outcomes of Original Grant:
The goal of our original funded grant was to use our alpha-synuclein assay to identify compounds that prevent conformational change to the fully open form of the monomeric protein. Spermine binding induces a fully extended alpha-synuclein conformation and this leads to a great increase in its aggregation. We successfully applied our assay to identify a number of compounds that prevent this conformational change and appear to stabilize the monomeric protein in its compact conformation.
Objectives for Supplemental Investigation:
The objectives of our supplemental study are to improve the potency of our compound hits by using a screening-by-catalog approach and our SHG assay. Secondary assays will also be performed to further validate the compounds. NMR studies of two lead compounds will be determined to provide co-structures and verification that the compounds stabilize alpha-synuclein in its compact conformation.
Importance of This Research for the Development of a New PD Therapy:
Aggregation of alpha-synuclein is thought to be causative of PD. Its rate is greatly accelerated in vitro by inducing the protein to form a fully extended conformation, in which interactions between the C- and N-termini, which appear to stabilize the protein, are disrupted. The premise of our work with MJFF is to develop compounds that stabilize the monomeric protein in its compact conformation. By studying alpha- synuclein monomers, we are focusing on the furthest upstream point in aggregation. Such compounds could be developed into powerful therapeutics for PD.
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.