Join CurePSP on this Webcast presented by Nature Research Custom
Protein aggregation is a hallmark of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s. However, the mechanisms linking aggregation to neurotoxicity remain poorly understood, partly because only limited information is available on the structure of these aggregates. Determining the atomic structures of these aggregates is crucial to understanding their formation, clearance and spread in the human body.
Furthermore, very little is known about the native structure of protein aggregates inside cells. This challenge is addressed utilizing the latest developments in cryo-electron tomography (cryo-ET). Thin lamellas of vitrified cells containing protein aggregates are prepared by cryo-focused ion beam (cryo-FIB) and subsequently imaged in three dimensions by cryo-ET.
During this webcast, we will explain how using cryo-EM to solve the structures to 3.4 Angstrom resolution of amyloid fibrils isolated from post-mortem brain tissue of patients with a range of neurological disorders can elucidate the molecular and structural basis of neurodegeneration. Additionally, we will show how cryo-ET allows for the analysis of aggregate structures within pristinely preserved cellular environments at molecular resolution to shed new light on the cellular mechanisms of neurodegeneration.
In this webcast, attendees will learn:
- About advances in cryo-TEM single particle analysis (SPA) for structure determination of protein complexes.
- How cryo-EM/SPA was applied to determine the first near-atomic resolution of filaments.
- The importance of atomic cryo-EM filament structure for drug design and the development of biomarkers for early detection.
- The technological developments that allow 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.
Meet The Speakers:
Dr. Anthony Fitzpatrick, Columbia University, New York
Dr. Anthony Fitzpatrick is an Assistant Professor of Biochemistry and Molecular Biophysics at the Zuckerman Institute, Columbia University, New York, USA. Previously, he was a Marie Curie International Outgoing Fellow at the Laboratory of Molecular Biology, University of Cambridge (2015–2017) and the California Institute of Technology (2012–2014). He has a biophysics background (PhD with Professor Christopher M. Dobson, University of Cambridge) and undertook postdoctoral training with Professors Helen Saibil in London, Robert G. Griffin at the Massachusetts Institute of Technology, Ahmed H. Zewail (Nobel Laureate) at the California Institute of Technology, and Sjors Scheres and Michel Goedert at the Laboratory of Molecular Biology, Cambridge. The research focus of the Fitzpatrick Lab is to determine the structure and behavior of patient-derived amyloid fibrils and, more generally, to understand the role of protein aggregation in vivo by identifying the cellular changes that occur in response to the formation, clearance and spread of fibrillar inclusions. The methods employed by his lab are largely experimental and include cryo-electron microscopy (cryo-EM), mass spectrometry, transcriptomics, microfluidics, magic angle spinning NMR and optical super-resolution microscopy.
Dr. Rubén Fernández-Busnadiego, Max Planck Institute of Biochemistry
Dr. Rubén Fernández-Busnadiego is a project group leader at the Max Planck Institute of Biochemistry in Martinsried, Germany. Rubén studied Physics at the Complutense University of Madrid and earned his PhD at the Max Planck Institute of Biochemistry studying synaptic structure by cryo-electron tomography (cryo-ET). After a postdoc at Yale University, he returned to Max Planck to lead a group investigating the structural mechanisms linking protein aggregation to neurodegeneration. Rubén’s group investigates the structural basis of toxic protein aggregation in neurodegenerative diseases such as Alzheimer’s or Huntington’s using cutting-edge electron microscopy techniques. This work is illuminating the pathogenic interactions of aggregates within their cellular environment at unprecedented resolution. His latest findings on how fibrillar huntingtinaggregates alter ER function in neurons have been recently published in Cell (Bäuerlein et al., Cell 2017).
Moderator: Dr Jayshan Carpen, Nature Research
Jayshan received his PhD in neurogenetics from the University of Surrey, UK. His doctoral thesis focused on identifying polymorphisms associated with diurnal preference and circadian sleep disorders. Jayshan worked as an events coordinator at the Royal Institution of Great Britain before moving to his current role in 2013 for Nature Research.
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