Mechanisms of selective cell vulnerability to protein assembly propagation in neurodegenerative disease
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The assembly of a small number of proteins into amyloid structures within neurons and, in some cases, glia underlies neurodegenerative disease. These proteins include TDP-43, tau and alpha-synuclein. Mutations in the genes encoding these proteins lead to assembly and inherited neurodegenerative diseases, demonstrating a causal role.
Protein assembly begins in discrete brain regions, from where it appears to propagate (spread and amplify) within connected brain networks in what has been described as a ‘prion-like’ manner, ultimately leading to neurodegeneration. The mechanisms of propagation are poorly understood. In particular it is not known why, in different diseases, assembly begins in different brain regions and propagates to different brain cell types, a phenomenon known as selective cell vulnerability.
This project aims to uncover mechanisms of selective cell vulnerability in neurodegenerative disease by studying the interactions between disease-specific assemblies and different neuronal and glial cell types. To do this, we will develop the use of correlative light-electron microscopy (CLEM), combined with genetic manipulation of cultured cells. We will take advantage of our ability to extract protein assemblies from human brain samples, preserving their disease-relevant structures, and our ability to model propagation in primary cell and tissue cultures, as well as in vivo.
Falcon B, Zivanov J, Zhang W, Murzin A, Garringer H, Vidal R, Crowther A, Newell K, Ghetti B, Goedert M and Scheres SHW. (2019)
Novel tau filament fold in chronic traumatic encephalopathy encloses hydrophobic molecules.
Nature 568: 420-423.
Falcon B, Zhang W, Schweighauser M, Murzin AG, Vidal R, Garringer HJ, Ghetti B, Scheres SHW & Goedert M. (2018)
Tau filaments from multiple cases of sporadic and inherited Alzheimer's disease adopt a common fold.
Acta Neuropathologica 136: 699-708.
Falcon B, Zhang W, Murzin AG, Murshudov G, Garringer HJ, Vidal R,Crowther RA, Ghetti B, Scheres SHW & Goedert M. (2018)
Structures of filaments from Pick’s disease reveal a novel tau protein fold.
Nature 561: 137-140.
Falcon B, Noad J, McMahon H, Randow F, Goedert M. (2018)
Galectin-8-mediated selective autophagy protects against seeded tau aggregation.
Journal of Biological Chemistry 293: 2438-2451.
Fitzpatrick AWP, Falcon B, He S, Murzin AG, Murshudov G, Garringer HJ, Crowther RA, Ghetti B, Goedert M & Scheres SHW. (2017)
Cryo-EM structures of tau filaments from Alzheimer’s disease.
Nature 547: 185-190.
Goedert M, Masuda-Suzukake M & Falcon B. (2017)
Like prions: the propagation of aggregated tau and α-synuclein in neurodegeneration.
Brain 140: 266-278.