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Ordered Assembly of Tau Protein and Neurodegeneration

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Tau Biology

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1184))

Abstract

Tau filaments with distinct morphologies and/or isoform compositions underlie a large number of human neurodegenerative diseases. Their formation is important, because dominantly inherited mutations in MAPT, the tau gene, cause frontotemporal dementia with abundant filamentous tau inclusions. Assembly of tau may begin in a specific region of the brain, from where it spreads to other areas. It remains to be seen if the molecular species underlying tau aggregate-mediated neurodegeneration and propagation are the same or different. In the brains of mice transgenic for human mutant P301S tau, small tau filaments are the predominant seed-competent species. It has been suggested that different conformers of assembled tau may give rise to different human tauopathies, but until recently, it was not possible to study this directly. Electron cryo-microscopy can now be used to determine high-resolution structures of amyloid filaments from human brain. Paired helical and straight tau filaments of Alzheimer’s disease are ultrastructural polymorphs. Each filament core is composed of two identical protofilaments extending from G273/304-E380 (in the numbering of the 441 amino acid isoform of human tau), which adopt a combined cross-β/β-helix structure. They comprise the ends of the first or second microtubule-binding repeat (R1 or R2), the whole of R3 and R4, as well as 12 amino acids after R4. By contrast, the core of the narrow filament of Pick’s disease consists of a single protofilament extending from K254-F378 of 3R tau, which adopts a cross-β structure. It comprises the last 21 amino acids of R1, all of R3 and R4, as well as 10 amino acids after R4. Wide tau filaments of Pick’s disease, which are in the minority, consist of two narrow filaments packed against each other. The tau filament folds of Alzheimer’s and Pick’s diseases appear to be conserved between different cases of disease. These findings show that filamentous tau adopts one fold in Alzheimer’s disease and a different fold in Pick’s disease, establishing the existence of distinct conformers.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Michel Goedert

  2. Clifford Allbutt Building, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK

    Maria Grazia Spillantini

Authors
  1. Michel Goedert
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  2. Maria Grazia Spillantini
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Correspondence to Michel Goedert .

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Editors and Affiliations

  1. Department of Life Sciences, Gakushuin University, Tokyo, Japan

    Akihiko Takashima

  2. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA

    Benjamin Wolozin

  3. University of Lille, INSERM, CHU-Lille, Alzheimer & Tauopathies, LabEx DISTALZ, Lille, France

    Luc Buee

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Goedert, M., Spillantini, M.G. (2019). Ordered Assembly of Tau Protein and Neurodegeneration. In: Takashima, A., Wolozin, B., Buee, L. (eds) Tau Biology. Advances in Experimental Medicine and Biology, vol 1184. Springer, Singapore. https://doi.org/10.1007/978-981-32-9358-8_1

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