Investigator:
Darci Trader, PhD
Name of Institution:
The Regents of the University of California, Irvine
Project Title:
Degradation of Alpha-Synuclein Oligomers via ByeTACs
Investigator Bio:
Dr. Darci Trader is an Associate Professor in the Department of Pharmaceutical Sciences at the University of California, Irvine. She earned her PhD in chemistry from Indiana University under the direction of Dr. Erin E. Carlson, where her research was focused on the development of chemoselective tools for the discovery and identification of natural products. She then pursued postdoctoral studies at The Wertheim UF Scripps Institute with Dr. Thomas Kodadek, studying the cell’s waste-disposal machinery, the proteasome. There, she developed novel ligands for proteasome subunits and new assays to monitor proteasome activity.
Dr. Trader began her independent career in 2016 as an Assistant Professor in the Department of Medicinal Chemistry and Molecular Pharmacology at Purdue University. In 2023, her lab moved to the University of California, Irvine, where her research focuses on developing diverse tools to better target and understand the proteasome.
Objectives/Background:
This study focuses on developing a way to help brain cells remove excess alpha-synuclein, a protein that builds up in Parkinson’s disease (PD) and contributes to nerve cell damage. To address this, we are designing small molecules – drug-like compounds – that act as a direct link between alpha-synuclein and the proteasome. These small molecules will be engineered to attach to alpha-synuclein and guide it directly to the proteasome for elimination.
Methods/Design:
The accumulation of alpha-synuclein in the brain is a key feature of PD pathology and contributes to the formation of toxic clusters in the cell. Normally, cells use a process called ubiquitination to tag proteins like alpha-synuclein for degradation. In PD, this system is often impaired, allowing harmful proteins to build up and damage brain cells. Current therapeutic strategies cannot directly remove excess alpha-synuclein build-up, highlighting the need for novel approaches to prevent accumulation.
This project focuses on developing small molecules that bypass the need for ubiquitination and instead directly guide alpha-synuclein clusters to the proteasome. Specifically, we will design molecules that attach alpha-synuclein to Rpn13, a subunit of the proteasome that recognizes proteins for degradation. Our early data suggests that the length of the linker between the alpha-synuclein-binding region and the Rpn13-binding region is critical for efficiently guiding protein clumps to the proteasome for removal.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The goal of this project is to clear the toxic proteins that can accumulate in PD and lead to neuron cell death. Our new method should be able to clear a wide variety of clustered species, helping cells to live healthier for longer. through a structured manual, instructional videos, and weekly remote coaching, providing a scalable and cost-effective solution for long-term PD management.