来自α-Synuclein凝聚物的中间纤维中的结构-毒性关系
Serene W Chen1, Joseph D Barritt1, Roberta Cascella2
1Department of Life Sciences, Imperial College London, London SW7 2AZ, U.K.
Journal of the American Chemical Society
|April 3, 2024
概括
研究人员确定了导致帕金森病神经退行的α-synuclein (αS) 中间毒性粉状纤维. 这些中间体在结构和生物学上与成熟的粉样蛋白不同,提供了新的治疗点.
科学领域:
- 神经科学
- 生物化学
- 结构生物学
背景情况:
- 阿尔法同核素 (αS) 异常聚合成粉样纤维素是帕金森病等神经退行性疾病的标志.
- 已知成熟的αS粉样蛋白的结构特征,但暂时的聚合中间体仍然不清楚.
研究的目的:
- 在αS聚合过程中形成的中间粉状纤维的结构和特性.
- 将这些中间体与成熟的粉样蛋白进行比较,并阐明它们在细胞毒性和膜结合中的作用.
主要方法:
- 固态核磁共振 (ssNMR)
- 冷电子显微镜 (冷电子显微镜)
- 生物物理测试
- 用神经细胞进行化
- 抗体的表征
- 设计突变物
主要成果:
- 描述了αS的过渡性粉体中间体,在从液体凝聚物到成熟纤维的聚合过程中形成.
- 这些中间体具有小的反平行β叶核和无序的N端区域,介导膜结合并诱导显著的细胞毒性.
- 成熟的粉样蛋白具有不同的特性:包括N端的重排核心,较低的细胞毒性和减少的膜相互作用.
结论:
- 该研究阐明了αS粉样中间体和成熟纤维之间的结构和功能差异.
- 确定了负责介质物种膜相互作用和细胞毒性的关键结构元素.
- 这些发现为αS介导的神经毒性和帕金森病的潜在治疗策略提供了洞察力.
更多相关视频
09:16Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation
Published on: June 26, 2018
7.6K
09:27Sequential Extraction of Soluble and Insoluble Alpha-Synuclein from Parkinsonian Brains
Published on: January 5, 2016
17.3K
相关概念视频
Amyloid Fibrils
9.5K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
9.5K
The Structure of Intermediate Filaments
4.0K
The intermediate filaments are one of three widely studied cytoskeletal filaments. They are so named as their diameter (10 nm) is in between that of microfilaments (7 nm) and the microtubules (25 nm). These filaments are highly stable and can remain intact when exposed to high salt concentrations and detergents. These filaments are responsible for providing stability and mechanical support to the cells. They also help in cell adhesion and maintaining tissue integrity.
Intermediate...
Intermediate...
4.0K
Formation of Intermediate Filaments
3.1K
Intermediate filaments are cytoskeletal proteins with higher tensile strength and flexibility than microfilaments and microtubules. Unlike the other two cytoskeletal proteins, intermediate filament formation lacks the enzymatic activity to hydrolyze nucleotides like ATP and GTP to generate energy for polymerization. Therefore, the formation of intermediate filaments is multistep self-assembly. The involvement of any accessory proteins in intermediate filament formation has not yet been...
3.1K
Types of Intermediate Filaments
3.7K
The intermediate filaments are an essential component of the cytoskeleton. Presently six types of intermediate filament have been identified. Type I and II are acidic and basic keratin proteins. Type III is of mesodermal origin and comprises four proteins: vimentin, desmin, glial fibrillary acidic protein (GFAP), and peripherin. Vimentin is commonly found in mesenchymal cells, desmin in muscle cells, GFAP in astrocytes, while peripherin is found in peripheral nervous system neurons (PNS). Type...
3.7K
Toxic Reactions: Overview
971
When toxic substances penetrate the human body, they disseminate to various tissues, undergoing metabolic changes. This process yields reactive metabolites that may covalently bind with specific target molecules, resulting in toxicity.
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
Toxicity falls into two primary categories: local and systemic.
Local toxicity appears at the exposure site, such as protein denaturation caused by caustic substances.
In contrast, systemic toxicity requires the toxic agent's absorption and distribution,...
971
