Structures of filaments from Pick’s disease reveal a novel tau protein fold

Benjamin Falcon, Wenjuan Zhang, Alexey G. Murzin, Garib Murshudov, Holly Garringer, Ruben Vidal, R. Anthony Crowther, Bernardino Ghetti, Sjors H.W. Scheres, Michel Goedert

Research output: Contribution to journalLetter

93 Citations (Scopus)

Abstract

The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer’s disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick’s disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer’s disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.

Original languageEnglish (US)
Pages (from-to)137-140
Number of pages4
JournalNature
Volume561
Issue number7721
DOIs
StatePublished - Sep 6 2018

Fingerprint

Pick Disease of the Brain
tau Proteins
Alzheimer Disease
Protein Isoforms
Cryoelectron Microscopy
Frontotemporal Dementia
Prions
Microtubules
Neurodegenerative Diseases
Phosphorylation
Brain

ASJC Scopus subject areas

  • General

Cite this

Falcon, B., Zhang, W., Murzin, A. G., Murshudov, G., Garringer, H., Vidal, R., ... Goedert, M. (2018). Structures of filaments from Pick’s disease reveal a novel tau protein fold. Nature, 561(7721), 137-140. https://doi.org/10.1038/s41586-018-0454-y

Structures of filaments from Pick’s disease reveal a novel tau protein fold. / Falcon, Benjamin; Zhang, Wenjuan; Murzin, Alexey G.; Murshudov, Garib; Garringer, Holly; Vidal, Ruben; Crowther, R. Anthony; Ghetti, Bernardino; Scheres, Sjors H.W.; Goedert, Michel.

In: Nature, Vol. 561, No. 7721, 06.09.2018, p. 137-140.

Research output: Contribution to journalLetter

Falcon, B, Zhang, W, Murzin, AG, Murshudov, G, Garringer, H, 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, vol. 561, no. 7721, pp. 137-140. https://doi.org/10.1038/s41586-018-0454-y
Falcon, Benjamin ; Zhang, Wenjuan ; Murzin, Alexey G. ; Murshudov, Garib ; Garringer, Holly ; Vidal, Ruben ; Crowther, R. Anthony ; Ghetti, Bernardino ; Scheres, Sjors H.W. ; Goedert, Michel. / Structures of filaments from Pick’s disease reveal a novel tau protein fold. In: Nature. 2018 ; Vol. 561, No. 7721. pp. 137-140.
@article{36017b97a62b4102a7fa3a12230596e2,
title = "Structures of filaments from Pick’s disease reveal a novel tau protein fold",
abstract = "The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer’s disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick’s disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer’s disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.",
author = "Benjamin Falcon and Wenjuan Zhang and Murzin, {Alexey G.} and Garib Murshudov and Holly Garringer and Ruben Vidal and Crowther, {R. Anthony} and Bernardino Ghetti and Scheres, {Sjors H.W.} and Michel Goedert",
year = "2018",
month = "9",
day = "6",
doi = "10.1038/s41586-018-0454-y",
language = "English (US)",
volume = "561",
pages = "137--140",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7721",

}

TY - JOUR

T1 - Structures of filaments from Pick’s disease reveal a novel tau protein fold

AU - Falcon, Benjamin

AU - Zhang, Wenjuan

AU - Murzin, Alexey G.

AU - Murshudov, Garib

AU - Garringer, Holly

AU - Vidal, Ruben

AU - Crowther, R. Anthony

AU - Ghetti, Bernardino

AU - Scheres, Sjors H.W.

AU - Goedert, Michel

PY - 2018/9/6

Y1 - 2018/9/6

N2 - The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer’s disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick’s disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer’s disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.

AB - The ordered assembly of tau protein into abnormal filamentous inclusions underlies many human neurodegenerative diseases1. Tau assemblies seem to spread through specific neural networks in each disease2, with short filaments having the greatest seeding activity3. The abundance of tau inclusions strongly correlates with disease symptoms4. Six tau isoforms are expressed in the normal adult human brain—three isoforms with four microtubule-binding repeats each (4R tau) and three isoforms that lack the second repeat (3R tau)1. In various diseases, tau filaments can be composed of either 3R or 4R tau, or of both. Tau filaments have distinct cellular and neuroanatomical distributions5, with morphological and biochemical differences suggesting that they may be able to adopt disease-specific molecular conformations6,7. Such conformers may give rise to different neuropathological phenotypes8,9, reminiscent of prion strains10. However, the underlying structures are not known. Using electron cryo-microscopy, we recently reported the structures of tau filaments from patients with Alzheimer’s disease, which contain both 3R and 4R tau11. Here we determine the structures of tau filaments from patients with Pick’s disease, a neurodegenerative disorder characterized by frontotemporal dementia. The filaments consist of residues Lys254–Phe378 of 3R tau, which are folded differently from the tau filaments in Alzheimer’s disease, establishing the existence of conformers of assembled tau. The observed tau fold in the filaments of patients with Pick’s disease explains the selective incorporation of 3R tau in Pick bodies, and the differences in phosphorylation relative to the tau filaments of Alzheimer’s disease. Our findings show how tau can adopt distinct folds in the human brain in different diseases, an essential step for understanding the formation and propagation of molecular conformers.

UR - http://www.scopus.com/inward/record.url?scp=85052877630&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85052877630&partnerID=8YFLogxK

U2 - 10.1038/s41586-018-0454-y

DO - 10.1038/s41586-018-0454-y

M3 - Letter

C2 - 30158706

AN - SCOPUS:85052877630

VL - 561

SP - 137

EP - 140

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7721

ER -