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Tar DNA binding protein-43 (TDP-43) associates with stress granules: Analysis of cultured cells and pathological brain tissue

Liu-Yesucevitz, L and Bilgutay, A and Zhang, YJ and Vanderwyde, T and Citro, A and Mehta, T and Zaarur, N and McKee, A and Bowser, R and Sherman, M and Petrucelli, L and Wolozin, B (2010) Tar DNA binding protein-43 (TDP-43) associates with stress granules: Analysis of cultured cells and pathological brain tissue. PLoS ONE, 5 (10).

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Tar DNA Binding Protein-43 (TDP-43) is a principle component of inclusions in many cases of frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). TDP-43 resides predominantly in the nucleus, but in affected areas of ALS and FTLD-U central nervous system, TDP-43 is aberrantly processed and forms cytoplasmic inclusions. The mechanisms governing TDP-43 inclusion formation are poorly understood. Increasing evidence indicates that TDP-43 regulates mRNA metabolism by interacting with mRNA binding proteins that are known to associate with RNA granules. Here we show that TDP-43 can be induced to form inclusions in cell culture and that most TDP-43 inclusions co-localize with SGs. SGs are cytoplasmic RNA granules that consist of mixed protein - RNA complexes. Under stressful conditions SGs are generated by the reversible aggregation of prion-like proteins, such as TIA-1, to regulate mRNA metabolism and protein translation. We also show that disease-linked mutations in TDP-43 increased TDP-43 inclusion formation in response to stressful stimuli. Biochemical studies demonstrated that the increased TDP-43 inclusion formation is associated with accumulation of TDP-43 detergent insoluble complexes. TDP-43 associates with SG by interacting with SG proteins, such as TIA-1, via direct protein-protein interactions, as well as RNA-dependent interactions. The signaling pathway that regulates SGs formation also modulates TDP-43 inclusion formation. We observed that inclusion formation mediated by WT or mutant TDP-43 can be suppressed by treatment with translational inhibitors that suppress or reverse SG formation. Finally, using Sudan black to quench endogenous autofluorescence, we also demonstrate that TDP-43 positive-inclusions in pathological CNS tissue co-localize with multiple protein markers of stress granules, including TIA-1 and eIF3. These data provide support for accumulating evidence that TDP-43 participates in the SG pathway.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Liu-Yesucevitz, L
Bilgutay, A
Zhang, YJ
Vanderwyde, T
Citro, A
Mehta, T
Zaarur, N
McKee, A
Bowser, R
Sherman, M
Petrucelli, L
Wolozin, B
ContributionContributors NameEmailPitt UsernameORCID
Date: 17 November 2010
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 5
Number: 10
DOI or Unique Handle: 10.1371/journal.pone.0013250
Refereed: Yes
MeSH Headings: Blotting, Western; Brain--cytology; Brain--metabolism; Brain--pathology; Cells, Cultured; Cytoplasm--metabolism; DNA-Binding Proteins--genetics; DNA-Binding Proteins--metabolism; Frontotemporal Lobar Degeneration--metabolism; Frontotemporal Lobar Degeneration--pathology; Gene Knockdown Techniques; Humans; Mutation
Other ID: NLM PMC2952586
PubMed Central ID: PMC2952586
PubMed ID: 20948999
Date Deposited: 22 Aug 2012 21:22
Last Modified: 25 Jan 2019 23:55


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