TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor

Colleen M. Dewey, Basar Cenik, Chantelle F. Sephton, Daniel R. Dries, Paul Mayer, Shannon K. Good, Brett A. Johnson, Joachim Herz, Gang Yu

Research output: Contribution to journalArticle

184 Scopus citations

Abstract

TDP-43, or TAR DNA-binding protein 43, is a pathological marker of a spectrum of neurodegenerative disorders, including amyotrophic lateral sclerosis and frontotemporal lobar degeneration with ubiquitin-positive inclusions. TDP-43 is an RNA/DNA-binding protein implicated in transcriptional and posttranscriptional regulation. Recent work also suggests that TDP-43 associates with cytoplasmic stress granules, which are transient structures that form in response to stress. In this study, we establish sorbitol as a novel physiological stressor that directs TDP-43 to stress granules in Hek293T cells and primary cultured glia. We quantify the association of TDP-43 with stress granules over time and show that stress granule association and size are dependent on the glycine-rich region of TDP-43, which harbors the majority of pathogenic mutations. Moreover, we establish that cells harboring wild-type and mutant TDP-43 have distinct stress responses: mutant TDP-43 forms significantly larger stress granules, and is incorporated into stress granules earlier, than wild-type TDP-43; in striking contrast, wild-type TDP-43 forms more stress granules over time, but the granule size remains relatively unchanged. We propose that mutant TDP-43 alters stress granule dynamics, which may contribute to the progression of TDP-43 proteinopathies.

Original languageEnglish (US)
Pages (from-to)1098-1108
Number of pages11
JournalMolecular and cellular biology
Volume31
Issue number5
DOIs
StatePublished - Mar 1 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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