Neurodegenerative Disease Research

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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