A cost-effective, high-throughput screening platform for modulator discovery of a-synuclein membrane interactions involved in neurodegenerative diseases

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Millions of people are afflicted with Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) every year. The lack of effective treatments to control these devastating diseases will result in a health, economic and social crisis in an aging society. Thus, numerous studies have been carried out to elucidate the molecular basis of AD/ADRD in the past few decades. Although the underlying mechanism remains enigmatic, it is well established that membrane damage by several proteins such as α-synuclein (α-syn) plays a critical role in disease progression and thus could be a potential target for therapeutic interventions. Despite extensive efforts to dissect the molecular mechanism of these protein-lipid interactions, effective drugs that can control them are scarce. We recently engineered a suite of nanodisc-based fluorescent probes that can robustly report the action of α-syn on the lipid bilayer. Building on these achievements, we now seek to further explore the use of this toolkit for modulator discovery to ameliorate membrane binding and remodeling activities of α-syn aggregates. If successful, the identified candidates will not only serve as valuable reagents to study the biology of α-syn, but also as potential therapeutics for AD/ADRD.