Abstract
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.
Original language | English |
---|---|
Pages (from-to) | 277-88 |
Number of pages | 12 |
Journal | EMBO Journal |
Volume | 30 |
Issue number | 2 |
DOIs | |
Publication status | Published - 19 Jan 2011 |
Keywords / Materials (for Non-textual outputs)
- Base Sequence
- Blotting, Northern
- Cell Line
- DNA-Binding Proteins/genetics
- Feedback, Physiological/physiology
- Gene Expression Regulation/genetics
- Gene Library
- Humans
- Immunoblotting
- Immunoprecipitation
- Molecular Sequence Data
- Plasmids/genetics
- Polymerase Chain Reaction
- RNA Interference
- RNA Processing, Post-Transcriptional/genetics
- RNA, Messenger/metabolism
- Sequence Analysis, DNA