Proteomic analyses reveal that loss of TDP-43 affects RNA processing and intracellular transport.
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.
Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, 1 Windsor Walk, London SE5 8AF, United Kingdom.
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Štalekar
Cardiovascular Division, King's College London BHF Centre, 125 Coldharbour Lane, London SE5 9NU, United Kingdom.
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Yin
Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia.
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Rebolj
Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, 1 Windsor Walk, London SE5 8AF, United Kingdom.
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Darovic
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, 1 Windsor Walk, London SE5 8AF, United Kingdom.
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Troakes
Cardiovascular Division, King's College London BHF Centre, 125 Coldharbour Lane, London SE5 9NU, United Kingdom.
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Mayr
Department of Clinical Neuroscience, Institute of Psychiatry, King's College London, 1 Windsor Walk, London SE5 8AF, United Kingdom.
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Shaw
Department of Biotechnology, Jožef Stefan Institute, Jamova 39, SI-1000 Ljubljana, Slovenia; Biomedical Research Institute BRIS, Puhova 10, SI-1000 Ljubljana, Slovenia. Electronic address: boris.rogelj@ijs.si.
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Rogelj
D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D053378:Chromogranin B / Q000378:metabolism; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D000090205:DNA Methyltransferase 3A; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D040901:Proteomics; D012313:RNA / Q000378:metabolism*; D028961:beta Karyopherins / Q000378:metabolism
D002352:Carrier Proteins; D053378:Chromogranin B; D004268:DNA-Binding Proteins; C000717967:DNMT3A protein, human; D009687:Nuclear Proteins; C000598624:TARDBP protein, human; C108121:TNPO1 protein, human; D028961:beta Karyopherins; C091775:ran-binding protein 1; D012313:RNA; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
RanBP1; TDP-43; amyotrophic lateral sclerosis; comparative proteomics; frontotemporal lobar degeneration; intracellular transport