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TDP-43 Is Directed to Stress Granules by Sorbitol, a Novel Physiological Osmotic and Oxidative Stressor ▿

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

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

Topics: Articles
Publisher: American Society for Microbiology (ASM)
OAI identifier: oai:pubmedcentral.nih.gov:3067820
Provided by: PubMed Central
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