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

每年有数百万人患有阿尔茨海默病和阿尔茨海默病相关痴呆（AD/ADRD）。缺乏有效的治疗方法来控制这些毁灭性的疾病，将导致老龄化社会的健康、经济和社会危机。因此，在过去的几十年里，人们进行了大量的研究来阐明AD/ADRD的分子基础。尽管潜在的机制仍然是谜，但已经确定的是，几种蛋白质如α-突触核蛋白（α-syn）对膜的损伤在疾病进展中起关键作用，因此可能是治疗干预的潜在靶点。尽管广泛的努力解剖这些蛋白质-脂质相互作用的分子机制，有效的药物，可以控制他们是稀缺的。我们最近设计了一套基于纳米圆盘的荧光探针，可以可靠地报告α-syn对脂质双分子层的作用。在这些成果的基础上，我们现在寻求进一步探索使用这个工具箱来发现调节剂，以改善α-syn聚集体的膜结合和重塑活性。如果成功，这些候选基因不仅可以作为α-syn生物学研究的重要试剂，而且还可以作为AD/ADRD的潜在治疗药物。

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.