Lectures and seminars Research Lecture at Nobel Forum: Cryo-EM Structures of Amyloid Filaments from the Human Brain
The lecture is held in English at the Nobel Forum by Professor Michel Goedert Professor at Cambridge University, UK.
Cryo-EM Structures of Amyloid Filaments from the Human Brain
The assembly of a small number of proteins into abundant amyloid filaments defines most human neurodegenerative diseases, including Alzheimer’s and Parkinson’s. The major proteins are tau, amyloid-beta, alpha-synuclein, transactive response DNA-binding protein 43 (TDP-43) and TATA-box binding protein-associated factor 15 (TAF15). Based largely on the study of familial forms of disease, the formation of abundant filaments or their mere presence is believed to result in the propagation of inclusions and neurodegeneration.
From 2017, in a collaboration with the group of Sjors Scheres at the MRC Laboratory of Molecular Biology, we are using electron cryo-microscopy (cryo-EM) to determine the structures of amyloid filaments from the human brain. These structures cannot be predicted using computational approaches. I will describe our work on tau, amyloid-beta and alpha-synuclein. So far, each sporadic disease is characterised by a specific fold, but several diseases can share the same fold. Differences between folds are between some diseases, not between individuals with a given disease. The work on filament structures from human brains has also shown that the known structures of tau, amyloid-beta and alpha-synuclein filaments assembled in vitro are different. To understand mechanisms of filament formation, it is essential to develop methods by which to assemble recombinant proteins into disease filaments. We have recently reconstituted the Alzheimer fold by assembling truncated or modified recombinant full-length human tau.
Neurodegenerative diseases used to be defined by clinicopathological criteria only. Our work is now providing a more precise structure-based classification that is essential for emerging approaches to develop disease-modifying therapies of these terrifying illnesses.
Michel Goedert, MD, PhD, is a Programme Leader at the Medical Research Council (MRC) Laboratory of Molecular Biology in Cambridge, United Kingdom and an Emeritus Honorary Professor at Cambridge University. A native of Luxembourg, he received an MD from Basel University (Switzerland) and a PhD from Cambridge University. He was Head of the Laboratory’s Neurobiology Division from 2003-2016. Goedert’s research, which focuses on the molecular underpinnings of neurodegenerative diseases, established the central roles of tau and alpha-synuclein amyloids in Alzheimer’s, Parkinson’s and other neurodegenerative diseases. Goedert’s work has been recognised by several awards, including the Brain Prize and a Royal Medal from the Royal Society. He is a member of the European Molecular Biology Organization, a Fellow of the Royal Society and a Fellow of the UK Academy of Medical Sciences.
Host: Sten Linnarsson, PhD, Professor of Molecular Systems Biology, Karolinska Institutet.
Contact: Ann-Mari Dumanski, Nobel Office, Nobel Forum, 08-524 87 800, nobelforum@nobelprizemedicine.org