相关实验视频

Updated: Jun 8, 2025

Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo

Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo

Published on: June 2, 2019

血清酸化模仿Aβ形成不同的,非交叉播种的纤维状形态

Kalyani Sanagavarapu¹, Georg Meisl², Veronica Lattanzi^1,3

¹Biochemistry and Structural Biology, Department of Chemistry, Lund University Lund Sweden sara.linse@biochemistry.lu.se.

Chemical science

|November 4, 2024

概括

化粉样β (Aβ) 的酸化显著降低了它的聚合. 修改后的Aβ42,特别是谷氨酸突变,显示出更慢的二次核和改变的纤维结构,影响阿尔茨海默病的病理学.

科学领域:

生物化学生物化学
神经科学是一个神经科学.
结构生物学结构生物学

背景情况:

氨基酸β (Aβ) 自组合成纤维是阿尔茨海默病 (AD) 的核心.
在AD聚合物中发现了翻译后的修饰,比如在Aβ位置8和26的酸化.
这些修改对Aβ聚合机制的确切影响尚不清楚.

研究的目的:

阐明Aβ42的聚合机制,在8位和26位具有型突变的Aβ42.
调查尺寸 (谷氨酸) 和尺寸/电荷 (谷氨酸) 模拟如何影响Aβ聚合倾向和动力学.
了解结构兼容性在二次核和纤维细胞形成中的作用.

主要方法:

合成和聚合测试的Aβ42变体与phosphomimic突变 (S8Q,S8E,S26Q,S26E).
播种实验以确认和量化二次核化速率.
低温电子显微镜 (cryo-EM) 和小角度X射线散射 (SAXS) 用于超结构分析.

主要成果:

与野生类型相比,所有Aβ42变体都显示出较低的聚合倾向,其中谷氨酸突变体表现出最大的减少.
二次核化仍然是主要的途径,但对于所有变体来说都显著减缓 (数量级或更多).
S26Q和S26E纤维没有交叉种子野生类型单体,而S8变体显示增加了协聚.
冷-EM和SAXS揭示了改变的S26Q纤维结构,节点到节点的距离增加,截面减少.

结论:

纤维和单体之间的结构兼容性对于二次核化效率至关重要.
微小的修改,如酸化,可以大大改变纤维结构和聚合潜力.
酸化可以通过促进独特的,非交叉播种的纤维细胞群来控制Aβ聚合,从而影响AD的发病.

更多相关视频

Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy

Analysis of β-Amyloid-induced Abnormalities on Fibrin Clot Structure by Spectroscopy and Scanning Electron Microscopy

Published on: November 30, 2018

Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation

Exogenous Administration of Microsomes-associated Alpha-synuclein Aggregates to Primary Neurons As a Powerful Cell Model of Fibrils Formation

Published on: June 26, 2018

相关概念视频

Amyloid Fibrils

Amyloid Fibrils

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,...

Phosphorylation

Phosphorylation

The addition or removal of phosphate groups from proteins is the most common chemical modification that regulates cellular processes. These modifications can affect the structure, activity, stability, and localization of proteins within cells as well as their interactions with other proteins.
During phosphorylation, protein kinases transfer the terminal phosphate group of ATP to specific amino acid side chains of substrate proteins. Serine, threonine, and tyrosine are the most commonly...

Protein and Protein Structure

Protein and Protein Structure

Proteins are one of the most abundant organic molecules in living systems and have the most diverse range of functions of all macromolecules. Proteins may be structural, regulatory, contractile, or protective. They may serve in transport, storage, or membranes; or they may be toxins or enzymes. Their structures, like their functions, vary greatly. They are all, however, amino acid polymers arranged in a linear sequence.
A protein's shape is critical to its function. For example, an enzyme...