Journal
NEUROSCIENCE
Volume 293, Issue -, Pages 157-170Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.neuroscience.2015.02.046
Keywords
TDP-43; RanBP1; amyotrophic lateral sclerosis; frontotemporal lobar degeneration; comparative proteomics; intracellular transport
Categories
Funding
- Slovenian Research Agency [J3-2356, J3-4026, J3-5502, P4-0127]
- Alzheimer's research UK
- National Institute of Health Research Biomedical Research Center at Guy's and St Thomas' National Health Service Foundation Trust
- King's College London
- King's College Hospital
- MRC [G0900635, G1100695, G0500289, G9318379, MC_G1000733, G0900688, MR/L016397/1] Funding Source: UKRI
- British Heart Foundation [FS/13/2/29892] Funding Source: researchfish
- Medical Research Council [MC_G1000733, G1100695, MR/L016397/1, G9318379, G0500289, G0900635, G0900688] Funding Source: researchfish
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Transactive response DNA-binding protein 43 (TDP-43) is a predominantly nuclear, ubiquitously expressed RNA and DNA-binding protein. It recognizes and binds to UG repeats and is involved in pre-mRNA splicing, mRNA stability and microRNA metabolism. TDP-43 is essential in early embryonic development but accumulates in cytoplasmic aggregates in amyotrophic lateral sclerosis (ALS) and tau-negative frontotemporal lobar degeneration (FTLD). It is not known yet whether cytoplasmic aggregates of TDP-43 are toxic or protective but they are often associated with a loss of TDP-43 from the nucleus and neurodegeneration may be caused by a loss of normal TDP-43 function or a gain of toxic function. Here we present a proteomic study to analyze the effect of loss of TDP-43 on the proteome. MS data are available via ProteomeXchange with identifier PXD001668. Our results indicate that TDP-43 is an important regulator of RNA metabolism and intracellular transport. We show that Ran-binding protein 1 (RanBP1), DNA methyltransferase 3 alpha (Dnmt3a) and chromogranin B (CgB) are downregulated upon TDP-43 knockdown. Subsequently, transportin 1 level is increased as a result of RanBP1 depletion. Improper regulation of these proteins and the subsequent disruption of cellular processes may play a role in the pathogenesis of the TDP-43 proteinopathies ALS and FTLD. (C) 2015 IBRO. Published by Elsevier Ltd. All rights reserved.
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