Modulation of α-Synuclein Fibrillation and Toxicity by 4-Phenylbutyric Acid.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
ACS Chemical Neuroscience Pub Date : 2025-03-19 Epub Date: 2025-02-28 DOI:10.1021/acschemneuro.4c00709
Kristos Baffour, Neelima Koti, Tony Nyabayo, Sathvika Balerao, Carissa Sutton, David Johnson, Rishi Patel, Santimukul Santra, Tuhina Banerjee
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引用次数: 0

Abstract

The protein misfolding and aggregation of α-synuclein (α-Syn) into neurotoxic amyloids underlies the pathogenesis of neurodegenerative diseases such as Parkinson's disease (PD). Emerging evidence suggests that 4-phenylbutyrate (PBA) may play a role as a potential chemical chaperone for targeting α-Syn aggregation, but its molecular mechanism remains largely unknown. Using in vitro assays, we demonstrate that PBA treatment alters the pattern of α-Syn aggregation, as evidenced by reduced formation of oligomeric species and its increased susceptibility to proteolytic cleavage under the influence of PBA. Proteinase K (PK) assays, surface plasmon resonance (SPR), Nile red assays, and cytotoxicity assays indicate that PBA interacts with the extensive hydrophobic contacts of α-Syn oligomers and significantly reduces α-Syn-amyloid-induced toxicity. Furthermore, using thioflavin T-based assays, we elucidated the kinetics of PBA-mediated modulation of α-Syn aggregation, highlighting its role in accelerating the formation of α-Syn amyloid fibrils. Molecular dynamics (MD) simulations suggest PBA's role in the destabilization of the C-terminus in α-Syn oligomers through multiple residue interactions. Collectively, our findings provide compelling evidence for the neuroprotective potential of PBA in targeting protein misfolding and aggregation in PD and suggest an avenue for disease-modifying interventions in neurodegenerative disorders.

4-苯基丁酸对α-突触核蛋白纤颤及其毒性的调节作用。
α-突触核蛋白(α-Syn)错误折叠和聚集成神经毒性淀粉样蛋白是神经退行性疾病如帕金森病(PD)发病机制的基础。越来越多的证据表明,4-苯基丁酸酯(PBA)可能作为一种潜在的靶向α-Syn聚集的化学伴侣,但其分子机制仍不清楚。通过体外实验,我们发现PBA处理改变了α-Syn聚集的模式,在PBA的影响下,寡聚物种类的形成减少,其对蛋白水解裂解的敏感性增加。蛋白酶K (PK)实验、表面等离子体共振(SPR)、尼罗红实验和细胞毒性实验表明,PBA与α-Syn寡聚物广泛的疏水接触相互作用,显著降低α-Syn淀粉样蛋白诱导的毒性。此外,利用基于硫黄素的实验,我们阐明了pba介导的α-Syn聚集调节的动力学,强调了其在加速α-Syn淀粉样原纤维形成中的作用。分子动力学(MD)模拟表明PBA通过多种残基相互作用参与α-Syn低聚物c端失稳。总的来说,我们的研究结果为PBA在PD中靶向蛋白质错误折叠和聚集的神经保护潜力提供了令人信服的证据,并为神经退行性疾病的疾病改善干预提供了一条途径。
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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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