Cholesterol Accelerates Aggregation of α-Synuclein Simultaneously Increasing the Toxicity of Amyloid Fibrils.

IF 4.1 3区 医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY ACS Chemical Neuroscience Pub Date : 2024-11-06 Epub Date: 2024-10-29 DOI:10.1021/acschemneuro.4c00501
Mikhail Matveyenka, Abid Ali, Charles L Mitchell, Harris C Brown, Dmitry Kurouski
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Abstract

A hallmark of Parkinson disease (PD) is a progressive degeneration of neurons in the substantia nigra pars compacta, hypothalamus, and thalamus. Although the exact etiology of irreversible neuronal degeneration is unclear, a growing body of experimental evidence indicates that PD could be triggered by the abrupt aggregation of α-synuclein (α-Syn), a small membrane protein that is responsible for cell vesicle trafficking. Phospholipids uniquely alter the rate of α-Syn aggregation and, consequently, change the cytotoxicity of α-Syn oligomers and fibrils. However, the role of cholesterol in the aggregation of α-Syn remains unclear. In this study, we used Caenorhabditis elegans that overexpressed α-Syn to investigate the effect of low (15%), normal (30%), and high (60%) concentrations of cholesterol on α-Syn aggregation. We found that an increase in the concentration of cholesterol in diets substantially shortened the lifespan of C. elegans. Using biophysical methods, we also investigated the extent to which large unilamellar vesicles (LUVs) with low, normal, and high concentrations of cholesterol altered the rate of α-Syn aggregation. We found that only lipid membranes with a 60% concentration of cholesterol substantially accelerated the rate of protein aggregation. Cell assays revealed that α-Syn fibrils formed in the presence of LUVs with different concentrations of cholesterol exerted very similar levels of cytotoxicity to rat dopaminergic neurons. These results suggest that changes in the concentration of cholesterol in the plasma membrane, which in turn could be caused by nutritional preferences, could accelerate the onset and progression of PD.

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胆固醇会加速α-突触核蛋白的聚集,同时增加淀粉样蛋白纤维的毒性。
帕金森病(PD)的特征之一是黑质、下丘脑和丘脑中的神经元逐渐退化。虽然不可逆神经元变性的确切病因尚不清楚,但越来越多的实验证据表明,帕金森病可能是由α-突触核蛋白(α-Syn)的突然聚集引发的。磷脂能独特地改变α-Syn的聚集速度,从而改变α-Syn寡聚体和纤维的细胞毒性。然而,胆固醇在α-Syn聚集中的作用仍不清楚。在这项研究中,我们利用过量表达α-Syn的秀丽隐杆线虫研究了低浓度(15%)、正常浓度(30%)和高浓度(60%)胆固醇对α-Syn聚集的影响。我们发现,饮食中胆固醇浓度的增加会大大缩短秀丽隐杆线虫的寿命。我们还使用生物物理方法研究了低浓度、正常浓度和高浓度胆固醇的大单拉米尔囊泡(LUV)在多大程度上改变了α-Syn的聚集率。我们发现,只有胆固醇浓度为 60% 的脂膜才会大大加快蛋白质的聚集速度。细胞实验显示,在含有不同浓度胆固醇的 LUV 存在下形成的 α-Syn 纤维对大鼠多巴胺能神经元的细胞毒性水平非常相似。这些结果表明,质膜中胆固醇浓度的变化可能会加速帕金森病的发病和进展,而这种变化又可能是由营养偏好引起的。
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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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