Inhibition of Phosphorylated Alpha-Synuclein Aggregation by Synthetic Protein Mimetics and Foldamers.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Neuroscience Pub Date : 2025-01-15 Epub Date: 2024-12-24 DOI:10.1021/acschemneuro.4c00546
Emily G Oldani, Nicholas H Stillman, Ryan A Dohoney, Charles Zuwu Baysah, Sunil Kumar
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Abstract

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.

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合成模拟蛋白和折叠蛋白对磷酸化α -突触核蛋白聚集的抑制作用。
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总称,包括帕金森病、路易小体痴呆和多系统萎缩。LB的主要成分之一是α-Synuclein残基129 (αS-129)的磷酸化修饰聚集体,αS-129是脑内多巴胺能神经元中表达的一种神经元蛋白。关于αS-129的作用有模棱两可的结果,表明它既参与增强病理,也参与功能修复病理。无论如何,对于基于lb的病理,一种潜在的治疗策略可能是识别αS和αS-129聚集的抑制剂。然而,据我们所知,还没有报道配体可以有效抑制αS-129的聚集。我们的团队最近发现了基于寡聚吡啶酰胺(合成蛋白质模拟物)和寡喹啉(折叠物)支架的αS聚集的有效拮抗剂。在各种PD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。本文对两种配体的αS-129聚集性和αS-129与αS-129共聚集性(αS/αS-129)进行了测试。在PD的生物物理和细胞模型中,这两种配体都是αS-129聚集和αS/αS-129共聚集的有效拮抗剂。这两种配体都能挽救由αS/αS-129共聚集介导的细胞毒性。据我们所知,这些是第一个有效抑制LB主要成分的配体。这一发现将有助于开发与聚集相关的突触核蛋白病的治疗见解。
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来源期刊
ACS Chemical Neuroscience
ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL
CiteScore
9.20
自引率
4.00%
发文量
323
审稿时长
1 months
期刊介绍: ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research
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