Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43

Yong Jie Zhang, Ya Fei Xu, Chad A. Dickey, Emanuele Buratti, Francisco Baralle, Rachel Bailey, Stuart Pickering-Brown, Dennis Dickson, Leonard Petrucelli

Research output: Contribution to journalArticle

267 Citations (Scopus)

Abstract

TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate ∼35 and ∼25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.

Original languageEnglish (US)
Pages (from-to)10530-10534
Number of pages5
JournalJournal of Neuroscience
Volume27
Issue number39
DOIs
StatePublished - Sep 26 2007
Externally publishedYes

Fingerprint

DNA-Binding Proteins
Caspases
Frontotemporal Lobar Degeneration
Amyotrophic Lateral Sclerosis
Frontotemporal Dementia
Caspase Inhibitors
Staurosporine
Neuroglia
Small Interfering RNA
Cytoplasm
Cell Culture Techniques
Gene Expression
Mutation
Genes

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Apoptosis
  • Caspase
  • Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U)
  • Progranulin
  • TDP-43

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Zhang, Y. J., Xu, Y. F., Dickey, C. A., Buratti, E., Baralle, F., Bailey, R., ... Petrucelli, L. (2007). Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. Journal of Neuroscience, 27(39), 10530-10534. https://doi.org/10.1523/JNEUROSCI.3421-07.2007

Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. / Zhang, Yong Jie; Xu, Ya Fei; Dickey, Chad A.; Buratti, Emanuele; Baralle, Francisco; Bailey, Rachel; Pickering-Brown, Stuart; Dickson, Dennis; Petrucelli, Leonard.

In: Journal of Neuroscience, Vol. 27, No. 39, 26.09.2007, p. 10530-10534.

Research output: Contribution to journalArticle

Zhang, YJ, Xu, YF, Dickey, CA, Buratti, E, Baralle, F, Bailey, R, Pickering-Brown, S, Dickson, D & Petrucelli, L 2007, 'Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43', Journal of Neuroscience, vol. 27, no. 39, pp. 10530-10534. https://doi.org/10.1523/JNEUROSCI.3421-07.2007
Zhang, Yong Jie ; Xu, Ya Fei ; Dickey, Chad A. ; Buratti, Emanuele ; Baralle, Francisco ; Bailey, Rachel ; Pickering-Brown, Stuart ; Dickson, Dennis ; Petrucelli, Leonard. / Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43. In: Journal of Neuroscience. 2007 ; Vol. 27, No. 39. pp. 10530-10534.
@article{ad25178a85e34d39a42dd4e4edd0b1c0,
title = "Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43",
abstract = "TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate ∼35 and ∼25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.",
keywords = "Amyotrophic lateral sclerosis (ALS), Apoptosis, Caspase, Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U), Progranulin, TDP-43",
author = "Zhang, {Yong Jie} and Xu, {Ya Fei} and Dickey, {Chad A.} and Emanuele Buratti and Francisco Baralle and Rachel Bailey and Stuart Pickering-Brown and Dennis Dickson and Leonard Petrucelli",
year = "2007",
month = "9",
day = "26",
doi = "10.1523/JNEUROSCI.3421-07.2007",
language = "English (US)",
volume = "27",
pages = "10530--10534",
journal = "Journal of Neuroscience",
issn = "0270-6474",
publisher = "Society for Neuroscience",
number = "39",

}

TY - JOUR

T1 - Progranulin mediates caspase-dependent cleavage of TAR DNA binding protein-43

AU - Zhang, Yong Jie

AU - Xu, Ya Fei

AU - Dickey, Chad A.

AU - Buratti, Emanuele

AU - Baralle, Francisco

AU - Bailey, Rachel

AU - Pickering-Brown, Stuart

AU - Dickson, Dennis

AU - Petrucelli, Leonard

PY - 2007/9/26

Y1 - 2007/9/26

N2 - TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate ∼35 and ∼25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.

AB - TAR DNA binding protein-43 (TDP-43) is the pathologic substrate of neuronal and glial inclusions in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U) and in amyotrophic lateral sclerosis (ALS). Mutations in the progranulin gene (PGRN) have been shown to cause familial FTLD-U. The relationship between progranulin and TDP-43 and their respective roles in neurodegeneration is unknown. We report that progranulin mediates proteolytic cleavage of TDP-43 to generate ∼35 and ∼25 kDa species. Suppression of PGRN expression with small interfering RNA leads to caspase-dependent accumulation of TDP-43 fragments that can be inhibited with caspase inhibitor treatment. Cells treated with staurosporine also induced caspase-dependent cleavage and redistribution of TDP-43 from its nuclear localization to cytoplasm. Altered cleavage and redistribution of TDP-43 in cell culture models are similar to findings in FTLD-U and ALS. The results suggest that abnormal metabolism of TDP-43 mediated by progranulin may play a pivotal role in neurodegeneration.

KW - Amyotrophic lateral sclerosis (ALS)

KW - Apoptosis

KW - Caspase

KW - Frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTDL-U)

KW - Progranulin

KW - TDP-43

UR - http://www.scopus.com/inward/record.url?scp=34848921202&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=34848921202&partnerID=8YFLogxK

U2 - 10.1523/JNEUROSCI.3421-07.2007

DO - 10.1523/JNEUROSCI.3421-07.2007

M3 - Article

C2 - 17898224

AN - SCOPUS:34848921202

VL - 27

SP - 10530

EP - 10534

JO - Journal of Neuroscience

JF - Journal of Neuroscience

SN - 0270-6474

IS - 39

ER -