Disturbance of Nuclear and Cytoplasmic TAR DNA-binding Protein (TDP-43) Induces Disease-like Redistribution, Sequestration, and Aggregate Formation*

By M. Winton, L. Igaz, Margaret M. Wong, L. Kwong, John Q. Trojanowski, V. Lee. Journal of Biological Chemistry, 2008

637 citations recorded by the source corpus.

TAR DNA-binding protein 43 (TDP-43) is the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Although normal TDP-43 is a nuclear protein, pathological TDP-43 is redistributed and sequestered as insoluble aggregates in neuronal nuclei, perikarya, and neurites. Here we recapitulate these pathological phenotypes in cultured cells by altering endogenous TDP-43 nuclear trafficking and by expressing mutants with defective nuclear localization (TDP-43-ΔNLS) or nuclear export signals (TDP-43-ΔNES). Restricting endogenous cytoplasmic TDP-43 from entering the nucleus or preventing its exit out of the nucleus resulted in TDP-43 aggregate formation. TDP-43-ΔNLS accumulates as insoluble cytoplasmic aggregates and sequesters endogenous TDP-43, thereby depleting normal nuclear TDP-43, whereas TDP-43-ΔNES forms insoluble nuclear aggregates with endogenous TDP-43. Mutant forms of TDP-43 also replicate the biochemical profile of pathological TDP-43 in FTLD-U/ALS. Thus, FTLD-U/ALS pathogenesis may be linked mechanistically to deleterious perturbations of nuclear trafficking and solubility of TDP-43.

Subfields: Genetics, Neurology

View Paper: https://www.semanticscholar.org/paper/b0af2a5a0b3b8277c2e5ca06e644311906e8aba6

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Citations in the corpus

Aberrant cleavage of TDP-43 enhances aggregation and cellular toxicity (2009, background): “For example, Winton and colleagues have shown that the exogenous expression of full-length TDP-43 with NLS mutations leads to the accumulation of cytoplasmic aggregates and the sequestration of endogenous TDP-43, thereby depleting normal nuclear TDP-43 (22).”
Converging mechanisms in ALS and FTD: Disrupted RNA and protein homeostasis (2013, positive): “TDP-43 can shuttle between the cytosol and the nucleus (Ayala et al., 2008; Winton et al., 2008), although the majority of TDP-43 appears to be nuclear in most cells at steady state.”
ALS‐associated fused in sarcoma (FUS) mutations disrupt Transportin‐mediated nuclear import (2010, background): “…Molecular Biology Organization The EMBO Journal VOL 29 | NO 16 | 2010 2847 the classical NLS-dependent importin a/b (karyopherin a/b1) pathway (Winton et al, 2008), was not affected by expression of the M9M inhibitor and remained nuclear even in cells with cytoplasmic FUS staining (Figure 5D).”
TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. (2010, background): “In various cell culture experiments, the expression of TDP-43 proteins carrying mutations that disrupt its NLS (amino acids 78–84) led to localization primarily within the cytoplasm (223,230,231).”
Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS (2010, positive): “TDP-43 is normally a nuclear protein but pathological inclusions contain cytoplasmic TDP-43 aggregates, suggesting that altered subcellular localization of the protein may be critical to disease pathogenesis 6 .”
Structural determinants of the cellular localization and shuttling of TDP-43 (2008, background): “As expected, disruption of the bipartite nuclear localization signal inhibited the ability of NLS1 and NLS2 to be imported into the mouse nuclei.”
Tar DNA Binding Protein-43 (TDP-43) Associates with Stress Granules: Analysis of Cultured Cells and Pathological Brain Tissue (2010, background): “cytoplasmic inclusions when expression is forced to the cytoplasm by removal of the nuclear localization signal [9,10].”