TDP-43 affects splicing profiles and isoform production of genes involved in the apoptotic and mitotic cellular pathways.
In recent times, high-throughput screening analyses have broadly defined the RNA cellular targets of TDP-43, a nuclear factor involved in neurodegeneration. A common outcome of all these studies is that changing the expression levels of this protein can alter the expression of several hundred RNAs within cells. What still remains to be clarified is which changes represent direct cellular targets of TDP-43 or just secondary variations due to the general role played by this protein in RNA metabolism. Using an HTS-based splicing junction analysis we identified at least six bona fide splicing events that are consistent with being controlled by TDP-43. Validation of the data, both in neuronal and non-neuronal cell lines demonstrated that TDP-43 substantially alters the levels of isoform expression in four genes potentially important for neuropathology: MADD/IG20, STAG2, FNIP1 and BRD8. For MADD/IG20 and STAG2, these changes could also be confirmed at the protein level. These alterations were also observed in a cellular model that successfully mimics TDP-43 loss of function effects following its aggregation. Most importantly, our study demonstrates that cell cycle alterations induced by TDP-43 knockdown can be recovered by restoring the STAG2, an important component of the cohesin complex, normal splicing profile.
International Centre for Genetic Engineering and Biotechnology (ICGEB), 34012 Trieste, Italy.
Laura
L
De Conti
International Centre for Genetic Engineering and Biotechnology (ICGEB), 34012 Trieste, Italy.
Maureen V
MV
Akinyi
Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 Trieste, Italy.
Ramiro
R
Mendoza-Maldonado
LNCIB-Laboratorio Nazionale del Consorzio Interuniversitario per le Biotecnologie, Laboratorio di Oncologia Molecolare, 34012 Trieste, Italy.
Maurizio
M
Romano
International Centre for Genetic Engineering and Biotechnology (ICGEB), 34012 Trieste, Italy.
Marco
M
Baralle
International Centre for Genetic Engineering and Biotechnology (ICGEB), 34012 Trieste, Italy buratti@icgeb.org.
Emanuele
E
Buratti
D017398:Alternative Splicing; D034961:Antigens, Nuclear / Q000235:genetics* / Q000378:metabolism; D017209:Apoptosis; D001665:Binding Sites; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D053418:Death Domain Receptor Signaling Adaptor Proteins / Q000235:genetics* / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008938:Mitosis; D020033:Protein Isoforms / Q000235:genetics; D000097722:Cohesins
D034961:Antigens, Nuclear; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D053418:Death Domain Receptor Signaling Adaptor Proteins; D020662:Guanine Nucleotide Exchange Factors; D020033:Protein Isoforms; C105852:MADD protein, human; C508565:STAG2 protein, human; D000097722:Cohesins; C000598624:TARDBP protein, human