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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.

 


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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.

 

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.

Applications

Drug discovery

Drug Discovery

Learn how to take advantage of rational drug design for many major drug target classes, leading to best-in-class drugs.

Techniques

Single Particle Analysis

Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.

Learn more ›

Cryo-Tomography

Cryo-electron tomography (cryo-ET) delivers both structural information about individual proteins as well as their spatial arrangements within the cell. This makes it a truly unique technique and also explains why the method has such an enormous potential for cell biology. Cryo-ET can bridge the gap between light microscopy and near-atomic-resolution techniques like single-particle analysis.

Learn more ›

Single Particle Analysis

Single particle analysis (SPA) is a cryo-electron microscopy technique that enables structural characterization at near-atomic resolutions, unraveling dynamic biological processes and the structure of biomolecular complexes/assemblies.

Learn more ›

Cryo-Tomography

Cryo-electron tomography (cryo-ET) delivers both structural information about individual proteins as well as their spatial arrangements within the cell. This makes it a truly unique technique and also explains why the method has such an enormous potential for cell biology. Cryo-ET can bridge the gap between light microscopy and near-atomic-resolution techniques like single-particle analysis.

Learn more ›

Products

Style Sheet for Instrument Cards Original
Thermo Scientific Tundra Cryo transmission electron microscope (TEM)

Tundra Cryo-TEM

  • Structural information at biologically relevant resolution
  • Space efficient and cost effective
  • Easy, iterative sample optimization
  • Unique AI algorithms for streamlined data collection
Thermo Scientific Glacios Cryo transmission electron microscope (TEM)

Glacios Cryo-TEM

  • Flexible Accelerating Voltage 80-200 kV
  • Industry-leading Autoloader for cryogenic sample manipulation
  • Small footprint
  • Enhanced ease-of-use
Thermo Scientific Krios G4 Cryo transmission electron microscope (TEM)

Krios G4 Cryo-TEM

  • Improved ergonomics
  • Fits more easily into new and existing labs
  • Maximized productivity and automation
  • Best image quality for high-resolution 3D reconstruction

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