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AR DNA-binding protein 43 (TDP-43) is normally a nuclear RNA-binding protein that exhibits a range of functions including regulation of alternative splicing, RNA trafficking, and RNA stability. However, in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved, and is mislocalized to the cytoplasm where it forms distinctive aggregates. We previously developed a mouse model expressing human TDP-43 with a mutation in its nuclear localization signal (ΔNLS-hTDP-43) so that the protein preferentially localizes to the cytoplasm. These mice did not exhibit a significant number of cytoplasmic aggregates, but did display dramatic changes in gene expression as measured by microarray, suggesting that cytoplasmic TDP-43 may be associated with a toxic gain-of-function. Here, we analyze new RNA-sequencing data from the ΔNLS-hTDP-43 mouse model, together with published RNA-sequencing data obtained previously from TDP-43 antisense oligonucleotide (ASO) knockdown mice to investigate further the dysregulation of gene expression in the ΔNLS model. This analysis reveals that the transcriptomic effects of the overexpression of the ΔNLS-hTDP-43 transgene are likely due to a gain of cytoplasmic function. Moreover, cytoplasmic TDP-43 expression alters transcripts that regulate chromatin assembly, the nucleolus, lysosomal function, and histone 3’ untranslated region (UTR) processing. These transcriptomic alterations correlate with observed histologic abnormalities in heterochromatin structure and nuclear size in transgenic mouse and human brains.
© 2015 Amlie-Wolf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Amlie-Wolf, A., Ryvkin, P., Tong, R., Dragomir, I., Suh, E., Xu, Y., Van Deerlin, V. M., Gregory, B. D., Kwong, L. K., Trojanowski, J. Q., Lee, V., Wang, L., & Lee, E. B. (2015). Transcriptomic Changes Due to Cytoplasmic TDP-43 Expression Revel Dysregulation of Histone Transcripts and Nuclear Chromatin. PLoS One, 10 http://dx.doi.org/10.1371/journal.pone.0141836
Additional FilesFig 1_Transcriptomic changes due to cytoplasmic TDP-43.pdf (370 kB)
Fig 2_Transcriptomic changes due to cytoplasmic TDP-43.pdf (79 kB)
Fig 3_Transcriptomic changes due to cytoplasmic TDO-43.pdf (816 kB)
fig 4_Transcriptomic changes due to cytoplasmic TDP-43.pdf (461 kB)
Table 1_Transcriptomic changes due to cytoplasmic TDP-43.pdf (185 kB)
Table 2_Transcriptomic changes due to cytoplasmic TDP-43.pdf (117 kB)
fig 5_Transcriptomic changes due to cytoplasmic TDP-43.pdf (503 kB)
Date Posted:10 July 2017
This document has been peer reviewed.