Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity

Yongjie Zhang, Ya Fei Xu, Casey Cook, Tania D Gendron, Paul Roettges, Christopher D. Link, Wen Lang Lin, Jimei Tong, Monica Castanedes-Casey, Peter Ash, Jennifer Gass, Vijayaraghavan Rangachari, Emanuele Buratti, Francisco Baralle, Todd E. Golde, Dennis W Dickson, Leonard Petrucelli

Research output: Contribution to journalArticle

330 Citations (Scopus)

Abstract

Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining his- topathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a ∼25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.

Original languageEnglish (US)
Pages (from-to)7607-7612
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number18
DOIs
StatePublished - May 5 2009

Fingerprint

DNA-Binding Proteins
Poisons
Inclusion Bodies
Phosphorylation
Frontotemporal Lobar Degeneration
RNA Splicing
Frontotemporal Dementia
Amyotrophic Lateral Sclerosis
Caspases
Nuclear Proteins
Ubiquitin
Neuroglia
Cell Death
Antibodies
Brain

Keywords

  • Amyotrophic lateral sclerosis
  • Caspase
  • Cell death frontotemporal lobar degeneration with ubiquitin-positive inclusions
  • Inclusion

ASJC Scopus subject areas

  • General

Cite this

Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. / Zhang, Yongjie; Xu, Ya Fei; Cook, Casey; Gendron, Tania D; Roettges, Paul; Link, Christopher D.; Lin, Wen Lang; Tong, Jimei; Castanedes-Casey, Monica; Ash, Peter; Gass, Jennifer; Rangachari, Vijayaraghavan; Buratti, Emanuele; Baralle, Francisco; Golde, Todd E.; Dickson, Dennis W; Petrucelli, Leonard.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 18, 05.05.2009, p. 7607-7612.

Research output: Contribution to journalArticle

Zhang, Y, Xu, YF, Cook, C, Gendron, TD, Roettges, P, Link, CD, Lin, WL, Tong, J, Castanedes-Casey, M, Ash, P, Gass, J, Rangachari, V, Buratti, E, Baralle, F, Golde, TE, Dickson, DW & Petrucelli, L 2009, 'Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 18, pp. 7607-7612. https://doi.org/10.1073/pnas.0900688106
Zhang, Yongjie ; Xu, Ya Fei ; Cook, Casey ; Gendron, Tania D ; Roettges, Paul ; Link, Christopher D. ; Lin, Wen Lang ; Tong, Jimei ; Castanedes-Casey, Monica ; Ash, Peter ; Gass, Jennifer ; Rangachari, Vijayaraghavan ; Buratti, Emanuele ; Baralle, Francisco ; Golde, Todd E. ; Dickson, Dennis W ; Petrucelli, Leonard. / Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 18. pp. 7607-7612.
@article{5e857cfb46ef42f0a4c9845e0c05113e,
title = "Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity",
abstract = "Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining his- topathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a ∼25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.",
keywords = "Amyotrophic lateral sclerosis, Caspase, Cell death frontotemporal lobar degeneration with ubiquitin-positive inclusions, Inclusion",
author = "Yongjie Zhang and Xu, {Ya Fei} and Casey Cook and Gendron, {Tania D} and Paul Roettges and Link, {Christopher D.} and Lin, {Wen Lang} and Jimei Tong and Monica Castanedes-Casey and Peter Ash and Jennifer Gass and Vijayaraghavan Rangachari and Emanuele Buratti and Francisco Baralle and Golde, {Todd E.} and Dickson, {Dennis W} and Leonard Petrucelli",
year = "2009",
month = "5",
day = "5",
doi = "10.1073/pnas.0900688106",
language = "English (US)",
volume = "106",
pages = "7607--7612",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "18",

}

TY - JOUR

T1 - Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity

AU - Zhang, Yongjie

AU - Xu, Ya Fei

AU - Cook, Casey

AU - Gendron, Tania D

AU - Roettges, Paul

AU - Link, Christopher D.

AU - Lin, Wen Lang

AU - Tong, Jimei

AU - Castanedes-Casey, Monica

AU - Ash, Peter

AU - Gass, Jennifer

AU - Rangachari, Vijayaraghavan

AU - Buratti, Emanuele

AU - Baralle, Francisco

AU - Golde, Todd E.

AU - Dickson, Dennis W

AU - Petrucelli, Leonard

PY - 2009/5/5

Y1 - 2009/5/5

N2 - Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining his- topathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a ∼25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.

AB - Inclusions of TAR DNA-binding protein-43 (TDP-43), a nuclear protein that regulates transcription and RNA splicing, are the defining his- topathological feature of frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-Us) and sporadic and familial forms of amyotrophic lateral sclerosis (ALS). In ALS and FTLD-U, aggregated, ubiquitinated, and N-terminally truncated TDP-43 can be isolated from brain tissue rich in neuronal and glial cytoplasmic inclusions. The loss of TDP-43 function resulting from inappropriate cleavage, translocation from the nucleus, or its sequestration into inclusions could play important roles in neurodegeneration. However, it is not known whether TDP-43 fragments directly mediate toxicity and, more specifically, whether their abnormal aggregation is a cause or consequence of pathogenesis. We report that the ectopic expression of a ∼25-kDa TDP-43 fragment corresponding to the C-terminal truncation product of caspase-cleaved TDP-43 leads to the formation of toxic, insoluble, and ubiquitin- and phospho-positive cytoplasmic inclusions within cells. The 25-kDa C-terminal fragment is more prone to phosphorylation at S409/S410 than full-length TDP-43, but phosphorylation at these sites is not required for inclusion formation or toxicity. Although this fragment shows no biological activity, its exogenous expression neither inhibits the function nor causes the sequestration of full-length nuclear TDP-43, suggesting that the 25-kDa fragment can induce cell death through a toxic gain-of-function. Finally, by generating a conformation-dependent antibody that detects C-terminal fragments, we show that this toxic cleavage product is specific for pathologic inclusions in human TDP-43 proteinopathies.

KW - Amyotrophic lateral sclerosis

KW - Caspase

KW - Cell death frontotemporal lobar degeneration with ubiquitin-positive inclusions

KW - Inclusion

UR - http://www.scopus.com/inward/record.url?scp=66149114101&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=66149114101&partnerID=8YFLogxK

U2 - 10.1073/pnas.0900688106

DO - 10.1073/pnas.0900688106

M3 - Article

C2 - 19383787

AN - SCOPUS:66149114101

VL - 106

SP - 7607

EP - 7612

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 18

ER -