title: TDP-43 is directed to stress granules by sorbitol, a novel physiological osmotic and oxidative stressor.
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.
authors.affiliation: Department of Neuroscience, University of Texas Southwestern Medical Center, 6000 Harry Hines Blvd., Dallas, TX 75390-9111, USA.
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Dewey
authors.forename: Basar
authors.initials: B
authors.lastname: Cenik
authors.forename: Chantelle F
authors.initials: CF
authors.lastname: Sephton
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Dries
authors.forename: Paul
authors.initials: P
authors.lastname: Mayer
authors.forename: Shannon K
authors.initials: SK
authors.lastname: Good
authors.forename: Brett A
authors.initials: BA
authors.lastname: Johnson
authors.forename: Joachim
authors.initials: J
authors.lastname: Herz
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
mesh_terms: D000595:Amino Acid Sequence; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001681:Biological Assay; D002460:Cell Line; D002478:Cells, Cultured; D003594:Cytoplasmic Granules / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009457:Neuroglia / Q000187:drug effects / Q000378:metabolism; D009997:Osmotic Pressure; D018384:Oxidative Stress; D051381:Rats; D013012:Sorbitol / Q000494:pharmacology*; D057177:TDP-43 Proteinopathies / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D013012:Sorbitol