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).
Abstract
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
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID  |
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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 | | | |
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Contributors: |
Contribution | Contributors Name | Email | Pitt Username | ORCID  |
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Editor | Bush, Ashley I. | UNSPECIFIED | UNSPECIFIED | UNSPECIFIED |
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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 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/13557 |
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