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 journalArticlepeer-review

282 Scopus citations

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

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)

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