SHORTCAST: Cryo-electron microscopy helps understanding protein aggregation in neurodegenerative diseases
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Ricardo Guerrero-Ferreira, Center for Cellular Imaging and NanoAnalytics (C-CINA), Basel, Switzerland and Rubén Fernández-Busnadiego, Max Planck Institute of Biochemistry, Martinsried, Germany will present their cryo-EM work on α-synuclein fibril structure and tomography of toxic protein aggregates inside cells.
By applying cryo-electron microscopy, their research lays the groundwork for a more comprehensive mechanistic understanding of aggregate-associated neurodegenerative diseases:
Topic #1: Structure of alpha-synuclein fibrils by cryo-electron microscopy
The aggregation of alpha-synuclein in intracellular inclusions such as Lewy bodies and Lewy neurites is a neuropathological characteristic of synucleinopathies, a group of progressive disorders that include dementia with Lewy bodies, multiple system atrophy and Parkinson’s disease.
We are able to utilize cryo-electron microscopy (cryo-EM) to determine the structure of alpha-synuclein fibrils to 3.4 Angstrom resolution. These fibrils are composed of two protofilaments, which allow us to hypothesize about the effects of familial Parkinson’s disease mutations on fibril structure, the mechanism of fibril growth, and the structural factors that confer fibril stability.
In this webinar, we will describe the cryo-EM structure of an alpha-synuclein fibril and discuss the implications of this fibril structure on amyloid fibril elongation and the rational design of biomarkers for early detection of synucleinopathies.
Attend this webinar to learn:
- How cryo-EM can be used to determine the structure of amyloid fibrils linked to neurodegenerative diseases.
- The importance of determining the structure of fibrils to shed light on their growth and aggregation.
- How the structure of alpha-synuclein fibrils can inform the rational design of biomarkers for early detection of synucleinopathies.
Topic #2: Unraveling the structure of toxic protein aggregates in situ by cryo-electron microscopy
Protein aggregation is a hallmark of many neurodegenerative diseases, including Huntington’s, Parkinson’s and amyotrophic lateral sclerosis. However, the mechanisms linking aggregation to neurotoxicity remain poorly understood, partly because only limited information is available on the native structure of protein aggregates inside cells.
We are addressing this challenge utilizing the latest developments in cryo-electron tomography (cryo-ET). We prepare thin lamellas of vitrified cells containing protein aggregates using cryo-focused ion beam (cryo-FIB), and subsequently image them in three dimensions by cryo-ET. This allows us to analyze aggregate structures within pristinely preserved cellular environments and at molecular resolution. In this webinar, we will discuss how recent results shed new light on the cellular mechanisms of neurodegeneration.
Attend this webinar to learn:
- The technological developments allowing high-resolution imaging of the cell interior by cryo-ET.
- The importance of determining the structure of protein aggregates in situ, i.e. within an intact cellular environment.
- How cryo-ET imaging of protein aggregates within cells illuminates their mechanisms of cytotoxicity.
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