Organised by

Prof Annalisa Pastore
Visiting Professor, Imperial College London

Dr Yu Ye
Senior Lecturer, Imperial College London

Dr Michael Grange
Group Leader, Rosalind Franklin Institute

19-20 November 2024

The Stadium Room, Scale Space, White City, 58 Wood Lane, London W12 7RZ


Protein structure underpins function and dysfunction in molecular processes. Seventy years since the first protein and DNA structures, we are now for the first time able to consider studying the structure of molecules directly in situ and to correlate atomic resolution with information obtained at the cellular, tissue and organ levels.

In this two-day workshop, jointly hosted by Imperial College London, the UK DRI, and the Rosalind Franklin Institute, participants delved into recent advances in the field and explored how these novel technologies address key neuroscientific research challenges. There were talks from world-leading experts who have made significant contributions to Structural Neuroscience, spanning atomic to organismal insights, as well as a poster session and drinks reception to catalyse collaborations.

Aims

  1. Discuss the frontier of structural biology in Neurosciences and Neurodegeneration, presenting the leading edge of current structural biology approaches to investigate neuronal function/misfunction.
  2. Reflect on the gaps in understanding that nascent structural approaches may address, and how a new era may be entered into that will permit a multiscale understanding of neuronal processes at different levels of resolution.

Programme

Tuesday 19 November

Day 1

Molecules and Atoms

09.30-10.05    Sandra Ribeiro Macedo (University of Porto) 
10.05-10.40    Sjors Scheres (MRC Laboratory of Molecular Biology)  
10.40-11.15     Janet Kumita (University of Cambridge)  
11.15-11.35      Coffee break
11.35-12.10     Lisa Cabrita (University College London)  
12.10-12.45     Benjamin Ryskeldi-Falcon (MRC Laboratory of Molecular Biology)
12.45-13.00    Liina Sirvio Michael Morton (Imperial College London, Selected Speaker)

13.00-14.00    Lunch

Enlarging the perspective

14.00-14.35    Louise Serpell (University of Sussex) 
14.35-15.10    Elena Seiderake (University of Oxford)    
15.10-15.45    David Klenerman (UK DRI at Cambridge)
15.45-16.05    Coffee break
16.05-16.40    Perdita Barran (University of Manchester)
16.40-16.55    Callie Glynn (Rosalind Franklin Institute, Selected Speaker)
16.55-17.10      Charlotte Hodson (Astex Pharmaceuticals, Selected Speaker)

17.00-19.00    Poster session and drinks reception

19.00-21.00    Buffet dinner

Wednesday 20 November

Day 2

Structural approaches in context

09.00-09.35   Pete Cullen (University of Bristol) 
09.35-10.10    Ruben Fernandez-Busnadiego (University of Göttingen) 
10.10-10.45    Sarah Mizielinska (UK DRI at King's College London) 
10.45-11.05     Coffee break
11.05-11.40     Naoko Mizuno (National Heart, Lung and Blood Institute) 
11.40-12.15     Tim Bartels (UK DRI at University College London) 
12.15-12.30     René Frank (University of Leeds, Selected Speaker)

12.30-13.30 Lunch
 
Multiscale imaging and neurons

13.30-14.05    Alexandra Pacureanu (European Synchrotron Radiation Facility, ESRF) 
14.05-14.40    Radu Aricescu (MRC Laboratory of Molecular Biology)
14.40-15.00    Coffee break
15.00-15.35     Judy Kim Brian Caffrey (The Rosalind Franklin Institute)
15.35-16.10      Claire Walsh (University College London)
16.10-16.25      Saira Hameed (The Rosalind Franklin Institute, Selected Speaker)
16.25-16.30     Wrap up

Speakers

Professor Radu Aricescu

MRC Laboratory of Molecular Biology, Cambridge, UK

Talk title: "The wide wild world of human GABAA receptors"

Radu Aricescu is an MRC Investigator and Programme Leader at the MRC Laboratory of Molecular Biology. He leads a research group that employs structural methods to explore the mechanisms of neuronal synapse formation and function, and develops methods for CNS engineering and repair. Radu completed undergraduate and MSc studies at the University of Bucharest, Romania, and received a PhD from the University College London. This was followed by postdoctoral training in structural biology at the University of Oxford, where he has also established his research group (2007-2017). Since 2022 he holds a joint appointment in industry (BioNTech UK).

Professor Perdita Barran

University of Manchester, UK

Talk title: "Adventures with Mass Spectrometry and Joy: Towards Development of a Quantitative MRM assay using Sebum to Diagnose Parkinson’s Disease"

Professor Perdita Barran is Chair of Mass Spectrometry in the Department of Chemistry at The University of Manchester, Director of the Michael Barber Centre for Collaborative Mass Spectrometry, and a member of the Manchester Institute of Biotechnology. She also serves as Deputy Chair of the UK Medical Research Council’s Infrastructure and Capital Advisory Group. Her research spans biological mass spectrometry, protein structure, molecular modeling, and Parkinson’s diagnostics, where she has contributed to advancements in HDX-MS and proteomics. Professor Barran has been recognized with awards such as the Theophilus Redwood Award (2019), University of Manchester Researcher of the Year (2020), and the ACS Measurement Science Lectureship (2021). During the COVID-19 pandemic, she initiated the COVID-19 Mass Spectrometry Coalition and served as Chief Advisor to the UK Government on mass spectrometry. A dedicated mentor, she has guided over 35 PhD students and 16 postdoctoral fellows, with more than 200 peer-reviewed publications and 4,000 citations. In 2021, she founded Sebomix Ltd., focusing on sebum as a diagnostic biofluid, particularly for Parkinson’s Disease.

2

Dr Tim Bartels

UK DRI Centre at University College London, UK

Talk title: "Lipid metabolism as a modulator of alpha-synuclein aggregation"

Dr. Tim Bartels initially finished his MSc in Chemistry and Medical Engineering in 2005 at the Technical University Munich. In 2008 he received his PhD in Biophysics working at the Adolf Butenandt Institute (Director Christian Haass) at the Ludwig-Maximilian University (supervisors Johannes Buchner and Klaus Beyer). He completed his postdoctoral training at the Center for Neurologic Diseases/Harvard Medical School with Dennis Selkoe in 2011, where he also held his first faculty positions (Instructor of Neurology 2012-2016, assistant professor 2016-2019). Since 2018 he is leading the program “Structure-Function Relationship in Neurodegeneration” at the Dementia Research Institute at the University College London. His lab is dedicated to the involvement of the different forms of the presynaptic protein alpha-synuclein in Parkinson’s Disease and Dementia with Lewy Bodies. Furthermore, is his lab interested in novel context specific pathways of protein folding/misfolding and the involvement of lipids, non-neuronal cells and the gut-brain axis in neurodegeneration.

Dr Lisa Cabrita

University College London, UK

Talk title: "Structural and mechanistic studies of co-translational protein misfolding on the ribosome"

Lisa Cabrita completed her PhD in Biochemistry and Molecular Biology in the Department of Biochemistry at Monash University in Melbourne, Australia studying serine proteinase inhibitors. She was then took up a C.J. Martin fellowship with Chris Dobson at the University of Cambridge where she worked on developing a recombinant system for studying protein folding on the ribosome. She then took up a postdoctoral position with John Christodoulou at University College London continuing these studies. In 2017, she took up an independent position at UCL where her research group focusses on understanding the molecular links between protein biosynthesis and dysfunction in human disease.

3

Professor Peter Cullen

University of Bristol, UK

Talk title: "Mechanistic basis of integral protein sorting through the neuronal endosomal network"

Peter Cullen is the Royal Society Noreen Murray Research Professor at the University of Bristol. He works on protein sorting and recycling in mammalian cells which plays a fundamental role in normal cell function. His rigorous mechanistic dissection of the endosomal network has provided the framework to understand and interpret the underlying de-regulation of endosomal cargo sorting observed in a broad array of human diseases. These include cardiovascular disease and neurological disorders, most notably Alzheimer disease and Parkinson disease, as well as metabolic disorders such a type 2 diabetes. His work has opened up new therapeutic targets for the treatment of these diseases.

Professor Ruben Fernandez-Busnadiego

University Medical Cente Göttingen, Germany

Talk title: "Structural cell biology of neurons"

Ruben studied Physics at the Complutense University of Madrid (Spain). Afterwards, he carried out a research fellowship in the lab of Marcellus Ubbink at Leiden University (The Netherlands), which sparked his curiosity for structural biology. For his PhD, he joined the department of Wolfgang Baumeister at the Max Planck Institute of Biochemistry (Germany), where he investigated the structure of the presynaptic terminal by cryo-electron tomography (cryo-ET). To dive deeper into the molecular mechanisms of neuronal function, he worked with Pietro De Camilli (Yale University, USA) as a postdoctoral fellow. Later, he returned to the Max Planck Institute of Biochemistry to start a group using cryo-ET to investigate in situ the structure of toxic protein aggregates within cells. In 2019, he joined the faculty of the University Medical Center Göttingen (Germany), where he continues to harness the latest electron microscopy technology to unravel the structural basis of cell function and pathological dysfunction.

4

Dr Brian Caffrey

Rosalind Franklin Institute, UK

Talk title: "Exploring Alternative Approaches in TEM for Liquid Phase Chemical Mapping and Wider Fields of View"

Brian Caffrey is a Postdoctoral Research Associate in the Correlated Imaging Theme of the Rosalind Franklin Institute (RFI). His research focuses on the application of advanced microscopy methods to probe the biomolecular basis of disease. At the RFI, he is developing liquid phase electron microscopy and electron spectroscopy methods for application in biology. Recently, this work was awarded the Postdoctoral Scholar Award at the Microscopy & Microanalysis conference 2024. His PhD work at the National Institutes of Health, USA and the University of British Columbia, Canada with Prof. Sriram Subramaniam, spanned a wide range of biological length scales using both light and electron microscopy methods from mitochondria distribution across millions of microns of human tissues to the atomic resolution of small molecules. He has a special interest in multimodal staining methods for high resolution imaging in cancer biology and microbiology.

Suggested reading:

Professor Sir David Klenerman

UK DRI Centre at Cambridge, UK

Talk title: "Imaging protein aggregates in neurodegenerative diseases"

David Klenerman is a physical chemist who graduated and completed his doctorate at Cambridge University working with Professor Ian Smith on infra-red chemiluminescence for his PhD in 1985. This was followed by postdoctoral research at Stanford University, California with Professor Dick Zare on high overtone chemistry. He then returned to the U.K. and worked for seven years for BP Research in their Laser Spectroscopy Group before returning to the Department of Chemistry, University of Cambridge, progressing to a Professorship. He is currently a Royal Society Glaxo Wellcome Professor of Molecular Medicine. At Cambridge his work has focussed on the development and application of physical methods, particularly laser spectroscopy and single molecule fluorescence, to biological and biomedical problems. He is a Fellow of the Royal Society and the Academy of Medical Sciences.

5

Dr Janet Kumita

University of Cambridge, UK

Talk title: "Developing targeted protein degradation strategies for neurodegenerative diseases"

Janet Kumita completed her undergraduate degree in Biochemistry at the University of Waterloo and her PhD in Chemistry at the University of Toronto. In 2003, she was awarded an NSERC Postdoctoral Fellowship and joined Professor Sir Christopher Dobson’s group (Department of Chemistry, University of Cambridge), working closely with the Dobson group for 17 years. In 2020 she moved to the Department of Pharmacology to work with Professor Laura Itzhaki. In January 2022, Janet was awarded an MRC Career Development Award and became a Group Leader in the Department of Pharmacology. Her research looks at deciphering the underlying mechanisms of protein self-assembly to find therapeutic strategies to combat neurodegenerative diseases.

Dr Sarah Mizielinska

UK DRI Centre at King’s College London, UK

Talk title: "Using single molecule, biophysical and cell approaches to unveil structure-function alterations to the nuclear pore in C9ORF72 TDP-43 proteinopathy"

Sarah has 14 years of experience in neurodegeneration research, specializing in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Her work has led to 27 publications, including a first-author paper in Science (2014). She received the UCL Early Careers Neuroscience Prize in 2015 and joined King’s College London in 2016, becoming a UK Dementia Research Institute (UK DRI) Fellow in 2017. Now co-leading the Motor Neuron Disease (MND) Theme within the UK DRI, her research focuses on the C9ORF72 gene mutation in FTD/ALS, revealing toxic arginine-rich polypeptides through innovative genetic tools. Sarah's ongoing work seeks to uncover mechanisms of neurotoxicity and connections to TDP-43 proteinopathy, using advanced microscopy and biophysical assays with cell and stem cell models.

Suggested reading:

 

6

Dr Naoko MIzuno

National Heart, Lung, and Blood Institute (NHLBI), USA

Talk title: "In situ structural mechanism of Epothilone B-induced CNS neuroregeneration by cryo-ET"

Naoko Mizuno graduated from the University of Tokyo, and received her Ph.D. in biophysics from the University of Tokyo/University of Texas Southwestern Medical Center. Prior to joining the NHLBI as a senior investigator, she spent 8 years as an independent group leader at the Max Planck Institute of Biochemistry, Martinsried in Germany. Mizuno lab aims to understand the molecular mechanisms governing specialized cell shapes, such as those of neurons, and blood cells. They visualize the key factors determining different cell morphologies using in situ cellular cryo-electron tomography in combination with interdisciplinary techniques such as single-particle cryo-EM, in vitro reconstitution and light microscopy.

Dr Alexandra Pacureanu

European Synchrotron Radiation Facility (ESRF), France

Talk title: "Contributions of cryogenic X-ray nanotomography to structural neuroscience"

Alexandra Pacureanu is leading the Nanoscale Neuroimaging unit at ESRF, the European Synchrotron. Her main interests are expanding the horizons of X-ray microscopy for bioimaging and developing image analysis methods for nanotomography. After obtaining a PhD in signal processing and X-ray imaging from INSA Lyon, France in 2012, she pursued initial postdoctoral work at Uppsala University and the Science for Life Laboratory in Sweden, where she developed image analysis methods for in-situ gene sequencing and high throughput microscopy until 2014. She then continued at the European Synchrotron working on development of X-ray cryogenic nanotomography for biological tissues and cells. In 2019 she was a visiting scientist in the Neurobiology department at Harvard Medical School in Boston, and a senior research fellow at the University College London and the Francis Crick Institute. She established her research group at the European Synchrotron in 2020.

Suggested reading:

7

Professor Sandra Ribeiro

University of Porto, Portugal

Talk title: "Inhibitors of Ataxin-3 aggregation delay disease onset in SCA3/MJD animal models"

Sandra de Macedo Ribeiro has a background in Structural Biology, holds a degree in Biochemistry from the University of Porto (Portugal) and a Ph.D. from the Technical University of Munich Germany. Her training in Protein Crystallography started in 1992 as an Erasmus student at the University of Aarhus (Denmark) and proceeded during her Ph.D research at the Max-Planck Institut fuer Biochemie, Martinsried, Germany. In 2001-2002, following a post-Doctoral fellowship at IBMC-CSIC (Barcelona, Spain), Sandra moved to the University of Algarve (Portugal) as a Biochemistry Professor and later to the Center of Neuroscience and Cell Biology (Coimbra, Portugal) where she lead the Protein Structure Group. In 2006, Sandra joined the Institute for Molecular and Cellular Biology (Porto, Portugal), where she leads the Protein Crystallography Group. Research in Sandra Macedo Ribeiro lab focuses on the structural and functional characterization of biomedically relevant proteins, with a special emphasis on understanding the modulatory role of intermolecular interactions on proteins associated with neurodegenerative diseases.

Suggested reading:

Dr Benjamin Ryskeldi-Falcon

MRC Laboratory of Molecular Biology, Cambridge, UK

Talk title: "Unexpected insights into ALS and FTD from cryo-EM"

Benjamin obtained his BSc in Human Genetics from University College London. He completed his graduate studies with Michel Goedert at the MRC Laboratory of Molecular Biology (LMB), receiving a PhD in Molecular Biology from the University of Cambridge. He subsequently carried out a postdoc with Michel Goedert and Sjors Scheres at the LMB, where he helped to determine the electron cryo-microscpopy (cryo-EM) structures of assembled tau in neurodegenerative diseases. Since October 2019, Benjamin has led a research group at the LMB, with a focus on the molecular mechanisms of RNA-binding protein assembly in neurodegenerative diseases. Benjamin is a Young Investigator at the European Molecular Biology Organisation, a Co-investigator at the UK Dementia Research Institute and a Vallee Scholar. For his research, Benjamin was awarded the Alzheimer’s Research UK Rising Star Award, the Breuer Foundation Alzheimer’s Research Award and the SCOR Young European Researcher Prize.

8

Dr Sjors Scheres

MRC Laboratory of Molecular Biology, Cambridge, UK

Talk title: "Molecular pathology of neurodegenerative diseases by cryo-EM of amyloids"

Sjors studied chemistry at Utrecht University, The Netherlands, where he also obtained his PhD in protein crystallography. He was a post-doc in the group of Jose-Maria Carazo in Madrid, before he started his group at the LMB in 2010. Since 2018, Sjors is also joint Head of the Structural Studies division. His main interests lie in the development of new methods for high-resolution cryo-EM structure determination and their application to amyloid filaments.

Suggested reading:

Professor Elena Seiradake

University of Oxford, UK

Talk title: "Molecular mechanisms in cortical development"

Elena Seiradake is a molecular biologist at Oxford University, affiliated with the Department of Biochemistry, Somerville College, and the Kavli Institute for Nanoscience Discovery. Her interest in molecular biology began during her PhD at EMBL, where she determined the crystal structures of adenovirus capsid proteins and their complexes and contributed to developing the antifungal drug Kerydin. In 2008, Elena joined Yvonne Jones' lab at Oxford to study neural cell guidance systems, including Eph/ephrin and Netrin-G/NGL. She established her own lab in 2014 within Oxford’s Department of Biochemistry, where her team applies X-ray crystallography and Cryo-EM to investigate brain development. Their interdisciplinary work, focused on how receptor signaling complexes guide neuronal migration, has led to key findings published in Cell (del Toro et al., 2020; Akkermans et al., 2022).

9

Professor Louise Serpell

University of Sussex, UK

Talk title: "Unravelling the spark that initiates protein misfolding in Alzheimer’s disease"

Professor Louise Serpell is a Professor of Biochemistry at the University of Sussex, UK and a Director of Sussex Neuroscience. Her work focusses on protein self-assembly and misfolding at the heart of neurodegenerative diseases and amyloidosis.  Louise started her work on amyloid fibril structure during her PhD at the University of Oxford, UK before moving to University of Toronto, Canada to focus on Alzheimer’s disease at the Centre for Neurodegenerative Diseases. She returned to UK to the Laboratory of Molecular Biology, MRC Centre in Cambridge and then took up a fellowship at the University of Cambridge. She has worked in Sussex for over 20 years. Her current work spans structural biology to cellular neuroscience to uncover the mechanisms that lead to neurodegeneration in aging diseases. 

Dr Claire Walsh

University College London, UK

Talk title: "New opportunities in Human Brain Atlasing through Hierarchical Phase Contrast Tomography"

Claire Walsh is an Early Career Academic at UCL’s Department of Mechanical Engineering, Director of the Human Organ Atlas Hub (HOAHub), and Co-director of the HiP-CT research team. Her work focuses on developing imaging techniques and analysis pipelines for computational models of human physiology. During the COVID-19 pandemic, she collaborated internationally to pioneer Hierarchical Phase-Contrast Tomography (HiP-CT) for studying lung microstructure, a technique soon applied to multiple organs and recognized with the ESRF Young Scientist of the Year award in 2021. Now, as HOAHub Director, she leads a global consortium of over 30 groups dedicated to expanding HiP-CT’s applications. She also co-leads a multi-modal imaging project integrating HiP-CT with human connectome atlases, in collaboration with the Martinos Center.

Suggested reading:

UK DRI