FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations

Manuela Neumann, Eva Bentmann, Dorothee Dormann, Ali Jawaid, Mariely Dejesus-Hernandez, Olaf Ansorge, Sigrun Roeber, Hans A. Kretzschmar, David G. Munoz, Hirofumi Kusaka, Osamu Yokota, Lee Cyn Ang, Juan Bilbao, Rosa V Rademakers, Christian Haass, Ian R A MacKenzie

Research output: Contribution to journalArticle

157 Citations (Scopus)

Abstract

Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.

Original languageEnglish (US)
Pages (from-to)2595-2609
Number of pages15
JournalBrain
Volume134
Issue number9
DOIs
StatePublished - Sep 2011

Fingerprint

RNA-Binding Protein EWS
Frontotemporal Lobar Degeneration
Amyotrophic Lateral Sclerosis
Sarcoma
Pathology
Mutation
TATA-Binding Protein Associated Factors
Ewing's Sarcoma
Proteins
Protein
Karyopherins
Cytoplasmic Granules
RNA-Binding Proteins
Cell Nucleus Active Transport
Inclusion Bodies
DNA-Binding Proteins

Keywords

  • amyotrophic lateral sclerosis
  • EWS
  • frontotemporal dementia
  • FUS
  • TAF15

ASJC Scopus subject areas

  • Clinical Neurology
  • Arts and Humanities (miscellaneous)

Cite this

Neumann, M., Bentmann, E., Dormann, D., Jawaid, A., Dejesus-Hernandez, M., Ansorge, O., ... MacKenzie, I. R. A. (2011). FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. Brain, 134(9), 2595-2609. https://doi.org/10.1093/brain/awr201

FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. / Neumann, Manuela; Bentmann, Eva; Dormann, Dorothee; Jawaid, Ali; Dejesus-Hernandez, Mariely; Ansorge, Olaf; Roeber, Sigrun; Kretzschmar, Hans A.; Munoz, David G.; Kusaka, Hirofumi; Yokota, Osamu; Ang, Lee Cyn; Bilbao, Juan; Rademakers, Rosa V; Haass, Christian; MacKenzie, Ian R A.

In: Brain, Vol. 134, No. 9, 09.2011, p. 2595-2609.

Research output: Contribution to journalArticle

Neumann, M, Bentmann, E, Dormann, D, Jawaid, A, Dejesus-Hernandez, M, Ansorge, O, Roeber, S, Kretzschmar, HA, Munoz, DG, Kusaka, H, Yokota, O, Ang, LC, Bilbao, J, Rademakers, RV, Haass, C & MacKenzie, IRA 2011, 'FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations', Brain, vol. 134, no. 9, pp. 2595-2609. https://doi.org/10.1093/brain/awr201
Neumann, Manuela ; Bentmann, Eva ; Dormann, Dorothee ; Jawaid, Ali ; Dejesus-Hernandez, Mariely ; Ansorge, Olaf ; Roeber, Sigrun ; Kretzschmar, Hans A. ; Munoz, David G. ; Kusaka, Hirofumi ; Yokota, Osamu ; Ang, Lee Cyn ; Bilbao, Juan ; Rademakers, Rosa V ; Haass, Christian ; MacKenzie, Ian R A. / FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations. In: Brain. 2011 ; Vol. 134, No. 9. pp. 2595-2609.
@article{d0f6cd463ea5436897750f22585d8575,
title = "FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations",
abstract = "Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.",
keywords = "amyotrophic lateral sclerosis, EWS, frontotemporal dementia, FUS, TAF15",
author = "Manuela Neumann and Eva Bentmann and Dorothee Dormann and Ali Jawaid and Mariely Dejesus-Hernandez and Olaf Ansorge and Sigrun Roeber and Kretzschmar, {Hans A.} and Munoz, {David G.} and Hirofumi Kusaka and Osamu Yokota and Ang, {Lee Cyn} and Juan Bilbao and Rademakers, {Rosa V} and Christian Haass and MacKenzie, {Ian R A}",
year = "2011",
month = "9",
doi = "10.1093/brain/awr201",
language = "English (US)",
volume = "134",
pages = "2595--2609",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - FET proteins TAF15 and EWS are selective markers that distinguish FTLD with FUS pathology from amyotrophic lateral sclerosis with FUS mutations

AU - Neumann, Manuela

AU - Bentmann, Eva

AU - Dormann, Dorothee

AU - Jawaid, Ali

AU - Dejesus-Hernandez, Mariely

AU - Ansorge, Olaf

AU - Roeber, Sigrun

AU - Kretzschmar, Hans A.

AU - Munoz, David G.

AU - Kusaka, Hirofumi

AU - Yokota, Osamu

AU - Ang, Lee Cyn

AU - Bilbao, Juan

AU - Rademakers, Rosa V

AU - Haass, Christian

AU - MacKenzie, Ian R A

PY - 2011/9

Y1 - 2011/9

N2 - Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.

AB - Accumulation of the DNA/RNA binding protein fused in sarcoma as cytoplasmic inclusions in neurons and glial cells is the pathological hallmark of all patients with amyotrophic lateral sclerosis with mutations in FUS as well as in several subtypes of frontotemporal lobar degeneration, which are not associated with FUS mutations. The mechanisms leading to inclusion formation and fused in sarcoma-associated neurodegeneration are only poorly understood. Because fused in sarcoma belongs to a family of proteins known as FET, which also includes Ewing's sarcoma and TATA-binding protein-associated factor 15, we investigated the potential involvement of these other FET protein family members in the pathogenesis of fused in sarcoma proteinopathies. Immunohistochemical analysis of FET proteins revealed a striking difference among the various conditions, with pathology in amyotrophic lateral sclerosis with FUS mutations being labelled exclusively for fused in sarcoma, whereas fused in sarcoma-positive inclusions in subtypes of frontotemporal lobar degeneration also consistently immunostained for TATA-binding protein-associated factor 15 and variably for Ewing's sarcoma. Immunoblot analysis of proteins extracted from post-mortem tissue of frontotemporal lobar degeneration with fused in sarcoma pathology demonstrated a relative shift of all FET proteins towards insoluble protein fractions, while genetic analysis of the TATA-binding protein-associated factor 15 and Ewing's sarcoma gene did not identify any pathogenic variants. Cell culture experiments replicated the findings of amyotrophic lateral sclerosis with FUS mutations by confirming the absence of TATA-binding protein-associated factor 15 and Ewing's sarcoma alterations upon expression of mutant fused in sarcoma. In contrast, all endogenous FET proteins were recruited into cytoplasmic stress granules upon general inhibition of Transportin-mediated nuclear import, mimicking the findings in frontotemporal lobar degeneration with fused in sarcoma pathology. These results allow a separation of fused in sarcoma proteinopathies caused by FUS mutations from those without a known genetic cause based on neuropathological features. More importantly, our data imply different pathological processes underlying inclusion formation and cell death between both conditions; the pathogenesis in amyotrophic lateral sclerosis with FUS mutations appears to be more restricted to dysfunction of fused in sarcoma, while a more global and complex dysregulation of all FET proteins is involved in the subtypes of frontotemporal lobar degeneration with fused in sarcoma pathology.

KW - amyotrophic lateral sclerosis

KW - EWS

KW - frontotemporal dementia

KW - FUS

KW - TAF15

UR - http://www.scopus.com/inward/record.url?scp=80052959701&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052959701&partnerID=8YFLogxK

U2 - 10.1093/brain/awr201

DO - 10.1093/brain/awr201

M3 - Article

VL - 134

SP - 2595

EP - 2609

JO - Brain

JF - Brain

SN - 0006-8950

IS - 9

ER -