Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue

By L. Liu‐Yesucevitz, Aylin Bilgutay, Yong-Jie Zhang, Tara Vanderwyde, Allison Citro, Tapan H. Mehta, N. Zaarur, Ann C. McKee, R. Bowser, M. Sherman and 2 more. PLoS ONE, 2010

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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.

Subfields: Molecular Biology, Neurology

View Paper: https://www.semanticscholar.org/paper/676f9f6d3e3f45cf9c29006625ea5f30792b521c

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Citations in the corpus

Protein Phase Separation: A New Phase in Cell Biology (2018, background): “Both the labile-to-stable gel [15] and liquid- to-solid [14, 16] transitions could explain the pathological conversion of SGs to aggregates in ALS [78], but their exact relation to both cellular SGs and aggregates remains undetermined.”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, positive): “…stress granules produced in a wide range of cell lines with varying stresses, including oxidative, osmotic, and heat stresses (Ayala et al., 2011a; Colombrita et al., 2009; Dewey et al., 2011; Freibaum et al., 2010; Liu-Yesucevitz et al., 2010; McDonald et al., 2011; Meyerowitz et al., 2011).”
Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis (2019, background): “TDP-43 protein is intricately associated with stress granule dynamics (Liu-Yesucevitz et al., 2010; Walker et al., 2013).”
Stress granules as crucibles of ALS pathogenesis (2013, background): “Moreover, elimination of either the first or both RNA-binding domains of TDP-43 reduces basal aggregation (Liu-Yesucevitz et al., 2010).”
The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease (2012, background): “Under situations of stress, TDP-43, FUS, and other RNA-binding proteins translocate from the nucleus to the cytoplasm and associate with stress granules (Bosco et al., 2010; Dormann et al., 2010; Liu-Yesucevitz et al., 2010).”