Journal
EMBO JOURNAL
Volume 30, Issue 2, Pages 277-288Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/emboj.2010.310
Keywords
3 ' UTR; hnRNP; mRNA stability; neurodegeneration; RNA-protein interaction
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Funding
- AriSLA
- European Union [SHG-CT-2005-518238]
- Medical Research Council [MC_U105185858] Funding Source: researchfish
- MRC [MC_U105185858] Funding Source: UKRI
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TAR DNA-binding protein (TDP-43) is an evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) involved in RNA processing, whose abnormal cellular distribution and post-translational modification are key markers of certain neurodegenerative diseases, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. We generated human cell lines expressing tagged forms of wild-type and mutant TDP-43 and observed that TDP-43 controls its own expression through a negative feedback loop. The RNA-binding properties of TDP-43 are essential for the autoregulatory activity through binding to 3' UTR sequences in its own mRNA. Our analysis indicated that the C-terminal region of TDP-43, which mediates TDP-43-hnRNP interactions, is also required for self-regulation. TDP-43 binding to its 3' UTR does not significantly change the pre-mRNA splicing pattern but promotes RNA instability. Moreover, blocking exosome-mediated degradation partially recovers TDP-43 levels. Our findings demonstrate that cellular TDP-43 levels are under tight control and it is likely that disease-associated TDP-43 aggregates disrupt TDP-43 self-regulation, thus contributing to pathogenesis. The EMBO Journal (2011) 30, 277-288. doi:10.1038/emboj.2010.310; Published online 3 December 2010
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