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Neurodegenerative diseases

Neurodegenerative diseases encompass a broad range of neurological disorders characterized by the progressive dysfunction and degradation of neurons in the central nervous system. This includes well-known pathologies such as Alzheimer’s, Parkinson’s, and Huntington’s Disease as well as Amyotrophic Lateral Sclerosis (ALS). While the physical manifestation of these diseases has been extensively observed and characterized, the molecular basis is still an area of active investigation.

By using structural biology, researchers have begun to unravel the molecular changes that lead to neurological disorder – these efforts, in turn, drive the development of therapeutics that can slow or stop the course of disease. Neurodegenerative diseases encompass a broad range of neurological disorders characterized by the progressive dysfunction and degradation of neurons in the central nervous system. This includes well-known pathologies such as Alzheimer’s, Parkinson’s, and Huntington’s Disease as well as Amyotrophic Lateral Sclerosis (ALS). While the physical manifestation of these diseases has been extensively observed and characterized, the molecular basis is still an area of active investigation.

Neurodegenerative disease research using cryo-EM

Among techniques that resolve three-dimensional protein structures, cryo-electron microscopy (cryo-EM) is comparatively new but fills a critical niche that is inaccessible to spectroscopy and crystallography. In cryo-EM, aqueous samples are vitrified, trapping the specimens in an amorphous layer of ice that preserves them in their near-native states. This avoids the need for crystallization, allowing for the structural analysis of challenging systems like membrane or flexible proteins with multiple conformations.

In recent years, cryo-EM technology has improved dramatically, enabling the characterization of large sample areas and macromolecular proteins. This is particularly important for neurodegenerative disease research, where disorders are often characterized by the agglomeration and precipitation of complex protein aggregates. Researchers have already utilized cryo-EM to uncover the atomic structures of numerous proteins associated with neurodegenerative diseases such as tau filaments, ɑ-synuclein fibrils, and amyloid ß aggregates, as well as small molecule drug candidates that bind to these structures.

 Learn how cryo-EM is untangling neurodegenerative disease research in our eBook

Structure-based drug design using cryo-EM

In general, protein structure and function correlate. By understanding the structural features of the protein aggregates implicated in neurodegenerative diseases, scientists can address how they form, interact with the cellular environment, and alter brain function. Membrane proteins and large macromolecular structures are challenging targets for X-ray crystallography and NMR spectroscopy. (E.g. while membrane proteins account for over 60% of drug targets, they only make up ~2% of existing crystal structures.) Cryo-EM techniques, meanwhile, do not require crystal growth, making them more flexible and capable of determining the structures of non-crystalline proteins. With cryo-EM, researchers can analyze the complex conformations, structures, and modified forms of proteins; multiple conformations can even be studied within a single sample.

Learn more about the wide range of targets that can be studied with cryo-EM on our drug discovery page.

 


Resources

Style Sheet for Komodo Tabs

 

Publications library

 

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Cryo-EM and development of ketamine-based antidepressants

46:29

Dr. Shujia Zhu and her group from the Chinese Academy of Sciences determined the first cryo-EM structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine, and glutamate. In this webinar she has shared how their structural findings, coupled with electrophysiological studies, pave the way for future development of NMDA receptor-based antidepressants.

Untangling neurodegenerative diseases using cryo-electron microscopy

59:46

Prof. Anthony Fitzpatrick, Columbia University, discusses how cryo-EM solves structures of amyloid fibrils from patient post-mortem brain tissue with a range of neurological disorders & elucidates the molecular/structural basis of neurodegeneration.

Unraveling the structure of toxic protein aggregates in situ by cryo-electron microscopy

19:49

Dr. Rubén Fernández-Busnadiego, MPI Biochemistry, discusses how cryo-electron tomography imaging of protein aggregates within cells illuminates their mechanisms of cytotoxicity.

Structure of alpha-synuclein fibrils by cryo-electron microscopy

17:50

Ricardo Guerrero-Ferreira, Univ. Basel, covers cryo-EM structure of alpha-synuclein fibril and implications of this fibril structure on amyloid fibril elongation and the rational design of biomarkers for early detection of synucleinopathies.

Tale of amyloid filaments in neurodegenerative diseases

01:01:48

Cryo-EM has been used to solve the structures of tau filaments extracted from neuropathologically diseased brain tissue. This webinar highlights how cryo-EM is being used to identify new tauopathies and our understanding of these diseases.

 

Publications library

 

Publications search tool ›
  • Search and find scientific papers relevant to your research.
     
Subscribe to the Monthly Publications Newsletter ›

Cryo-EM and development of ketamine-based antidepressants

46:29

Dr. Shujia Zhu and her group from the Chinese Academy of Sciences determined the first cryo-EM structures of human GluN1-GluN2A and GluN1-GluN2B NMDA receptors in complex with S-ketamine, glycine, and glutamate. In this webinar she has shared how their structural findings, coupled with electrophysiological studies, pave the way for future development of NMDA receptor-based antidepressants.

Untangling neurodegenerative diseases using cryo-electron microscopy

59:46

Prof. Anthony Fitzpatrick, Columbia University, discusses how cryo-EM solves structures of amyloid fibrils from patient post-mortem brain tissue with a range of neurological disorders & elucidates the molecular/structural basis of neurodegeneration.

Unraveling the structure of toxic protein aggregates in situ by cryo-electron microscopy

19:49

Dr. Rubén Fernández-Busnadiego, MPI Biochemistry, discusses how cryo-electron tomography imaging of protein aggregates within cells illuminates their mechanisms of cytotoxicity.

Structure of alpha-synuclein fibrils by cryo-electron microscopy

17:50

Ricardo Guerrero-Ferreira, Univ. Basel, covers cryo-EM structure of alpha-synuclein fibril and implications of this fibril structure on amyloid fibril elongation and the rational design of biomarkers for early detection of synucleinopathies.

Tale of amyloid filaments in neurodegenerative diseases

01:01:48

Cryo-EM has been used to solve the structures of tau filaments extracted from neuropathologically diseased brain tissue. This webinar highlights how cryo-EM is being used to identify new tauopathies and our understanding of these diseases.

Applications

使用冷冻电镜进行药物发现研究

药物发现

学习如何借助冷冻电镜,将合理的药物设计用于多种主要的药物靶点,进而开发出一流的药物。

Techniques

单颗粒分析

单颗粒分析(SPA)是一种冷冻电镜技术,可实现近原子分辨率的结构表征,揭示动态生物学过程以及生物分子复合物/组装体的结构。

了解更多 ›

冷冻电子断层扫描

冷冻电子断层扫描(cryo-ET)既能够提供单个蛋白的结构信息,又能够提供它们在细胞内的空间排列信息。这使该方法成为一种真正独特的技术,在细胞生物学领域具有巨大的潜力。冷冻ET可以将光学显微镜和近原子分辨率技术(如单颗粒分析)结合在一起。

了解更多 ›

单颗粒分析

单颗粒分析(SPA)是一种冷冻电镜技术,可实现近原子分辨率的结构表征,揭示动态生物学过程以及生物分子复合物/组装体的结构。

了解更多 ›

冷冻电子断层扫描

冷冻电子断层扫描(cryo-ET)既能够提供单个蛋白的结构信息,又能够提供它们在细胞内的空间排列信息。这使该方法成为一种真正独特的技术,在细胞生物学领域具有巨大的潜力。冷冻ET可以将光学显微镜和近原子分辨率技术(如单颗粒分析)结合在一起。

了解更多 ›

Products

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Tundra Cryo-TEM

  • 生物学相关分辨率下的结构信息
  • 空间利用率高且经济划算
  • 轻松的迭代样品优化
  • 用于精简数据收集的独特 AI 算法

Glacios 冷冻 TEM

  • 可变的加速电压 80-200 kV
  • 用于冷冻样品操作的行业领先的自动加载器
  • 占地面积小
  • 增强易用性:

Krios G4 Cryo-TEM

  • 改进的人体工程学
  • 可更轻松放进新建或现有的实验室
  • 极大提高生产率和自动化水平
  • 用于高分辨率 3D 重构的最佳成像质量

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