Oldani Emily G, Stillman Nicholas H, Dohoney Ryan A, Baysah Charles Zuwu, Kumar Sunil
Department of Chemistry and Biochemistry, University of Denver, Denver, Colorado 80210, United States.
The Knoebel Institute for Healthy Aging, University of Denver, Denver, Colorado 80210, United States.
ACS Chem Neurosci. 2025 Jan 15;16(2):152-160. doi: 10.1021/acschemneuro.4c00546. Epub 2024 Dec 24.
The formation of Lewy bodies (LB) is a pathological hallmark for synucleinopathies, which is an umbrella term for many diseases, including Parkinson's disease, Lewy body dementia, and multiple system atrophy. One of the main components of LB is the aggregates of phosphorylated modification of α-Synuclein at residue 129 (αS-129), a neuronal protein expressed in the dopaminergic neurons in the brain. There are equivocal results about the role of αS-129, suggesting its involvement in both potentiating pathology and a functional role to rescue pathology. Regardless, a potential therapeutic strategy for LB-based pathologies could be the identification of inhibitors of both αS and αS-129 aggregation. However, to the best of our knowledge, there are no reports of ligands that can potently inhibit the aggregation of αS-129. Our group has recently identified potent antagonists of αS aggregation based on the oligopyridylamide (synthetic protein mimetics) and oligoquinoline (foldamers) scaffolds. Both ligands were potent antagonists of αS aggregation-mediated disease phenotypes in various PD models. Here, we tested both ligands against αS-129 aggregation and the coaggregation of αS and αS-129 (αS/αS-129). Both ligands were potent antagonists of αS-129 aggregation and coaggregation of αS/αS-129 in biophysical and cellular models of PD. Both ligands rescued cell toxicity mediated by the coaggregation of αS/αS-129. To the best of our knowledge, these are the first ligands that potently inhibit the major component of LB. This finding will aid in the development of therapeutic insights into aggregation-related synucleinopathies.
路易小体（LB）的形成是突触核蛋白病的病理标志，突触核蛋白病是许多疾病的统称，包括帕金森病、路易体痴呆和多系统萎缩。LB的主要成分之一是α-突触核蛋白第129位残基（αS-129）磷酸化修饰的聚集体，α-突触核蛋白是一种在大脑多巴胺能神经元中表达的神经元蛋白。关于αS-129的作用存在矛盾的结果，表明它既参与增强病理过程，又具有挽救病理的功能作用。无论如何，针对基于LB的病理的潜在治疗策略可能是鉴定αS和αS-129聚集的抑制剂。然而，据我们所知, 尚无能够有效抑制αS-129聚集的配体的报道。我们小组最近基于寡聚吡啶酰胺（合成蛋白质模拟物）和寡聚喹啉（折叠体）支架鉴定出了有效的αS聚集拮抗剂。在各种帕金森病模型中，这两种配体都是αS聚集介导的疾病表型的有效拮抗剂。在此，我们测试了这两种配体对αS-129聚集以及αS和αS-129（αS/αS-129）共聚集的作用。在帕金森病的生物物理和细胞模型中，这两种配体都是αS-129聚集以及αS/αS-129共聚集的有效拮抗剂。这两种配体都挽救了由αS/αS-129共聚集介导的细胞毒性。据我们所知，这些是首批能够有效抑制LB主要成分的配体。这一发现将有助于深入了解与聚集相关的突触核蛋白病的治疗方法。
