Distinct conformers of assembled tau in Alzheimer’s and Pick’s diseases

Michel Goedert, Benjamin Falcon, Wenjuan Zhang, Bernardino Ghetti, Sjors H.W. Scheres

Research output: Contribution to journalArticle

Abstract

Tau filaments with distinct morphologies and/or isoform compositions underlie a large number of human neurodegenerative diseases. In conjunction with experimental studies, this has led to the suggestion that conformers of aggregated tau exist. Electron cryo-microscopy can be used to determine high-resolution structures of amyloid filaments from human brain. Paired helical and straight tau filaments of Alzheimer’s disease (AD) 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, and 12 amino acids after R4. In contrast, the core of the narrow filaments of Pick’s disease (PiD) 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, and 10 amino acids after R4. Wide tau filaments of PiD, which are in the minority, consist of two narrow filaments packed against each other. The tau filament folds of AD and PiD appear to be conserved between different cases of disease. These findings show that filamentous tau adopts one fold in AD and a different fold in PiD, establishing the existence of distinct conformers.

Original languageEnglish (US)
Pages (from-to)163-171
Number of pages9
JournalCold Spring Harbor Symposia on Quantitative Biology
Volume83
DOIs
StatePublished - Jan 1 2018

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Pick Disease of the Brain
Alzheimer Disease
Amino Acids
Protein Isoforms
Cryoelectron Microscopy
Amyloid
Microtubules
Neurodegenerative Diseases
Neurodegenerative diseases
Brain
Polymorphism
Microscopic examination

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

Distinct conformers of assembled tau in Alzheimer’s and Pick’s diseases. / Goedert, Michel; Falcon, Benjamin; Zhang, Wenjuan; Ghetti, Bernardino; Scheres, Sjors H.W.

In: Cold Spring Harbor Symposia on Quantitative Biology, Vol. 83, 01.01.2018, p. 163-171.

Research output: Contribution to journalArticle

Goedert, Michel ; Falcon, Benjamin ; Zhang, Wenjuan ; Ghetti, Bernardino ; Scheres, Sjors H.W. / Distinct conformers of assembled tau in Alzheimer’s and Pick’s diseases. In: Cold Spring Harbor Symposia on Quantitative Biology. 2018 ; Vol. 83. pp. 163-171.
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