Structural diversity and functional implications of the eukaryotic TDP gene family

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

“…36 Finally, the glycine-rich C-terminal domain binds several heterogeneous nuclear ribonucleoproteins involved in the biogenesis of mRNA. 37,38 Thus, while the physiological functions of TDP-43 are as yet incompletely characterized, TDP-43, and in particular the C-terminal domain, appears to function in the regulation of gene expression. 34 The fact that both the Gly298Ser and Gly290Ala mutations identified here, as well as the Gly294Ala TARDBP mutation recently identified 27,28 all involve Gly residues within 10 aa of each other in the C-terminal domain of TDP-43, suggests that all three variants may cause disease through similar mechanisms.…”

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

“…Among mammals, zebrafish and flies, the protein sequence, biochemical properties and biological functions of TDP-43 are well conserved. In the nucleus, TDP-43 forms visible 50-250-nm granules that serve as a scaffold to link other functionally related sub-compartments, and participates in transcriptional repression as well as alternative splicing [9][10][11][12] . TDP-43 specifically binds to the UG repeat sequences in RNA, altering pre-mRNA splicing of cystic fibrosis transmembrane conductance regulator (CFTR) and may associate with long non-coding RNA to regulate nuclear speckle or paraspeckle 11,13 .…”

“…TDP-43 specifically binds to the UG repeat sequences in RNA, altering pre-mRNA splicing of cystic fibrosis transmembrane conductance regulator (CFTR) and may associate with long non-coding RNA to regulate nuclear speckle or paraspeckle 11,13 . TDP-43 mutants lacking a C-terminal glycine-rich region fail to excise exon 9 in the CFTR gene 9 , but how TDP-43 C terminus governs exon 9 skipping of CFTR, as well as its role in pathogenesis of TDP-43 proteinopathies, is still unknown. Given that the TDP-43 C terminus binds directly to heterogeneous nuclear ribonucleoprotein (hnRNP) A1 and hnRNP A2/B1 in pull-down assays 14 , the loss of association between TDP-43 and the hnRNPs has been proposed as a possible mechanism behind TDP-43 proteinopathies, causing aberrant pre-mRNA splicing or mislocalisation of TDP-43.…”

Staurosporine Induced Apoptosis Rapidly Downregulates TDP-43 in Glioma Cells

“…Under physiological conditions, functions of TDP-43 are associated with various pathways by binding to DNA, RNA or other nuclear proteins (Buratti et al, 2001;Buratti et al, 2004;Ayala et al, 2005;Mercado et al, 2005). It was reported that TDP-43 can recognize the intronic UG tract of CFTR pre-mRNA, thusly promoting skipping of exon 9 in CFTR mRNA (Wang et al, 2004;Ayala et al, 2006;Buratti et al, 2008), suggesting its role in RNA splicing regulation. TDP-43 also can interact with many other splicing related protein Freibaum et al, 2010) via the C-terminal glycine-rich domain of the protein (Wang et al, 2004;Ayala et al, 2005).…”

“…It was reported that TDP-43 can recognize the intronic UG tract of CFTR pre-mRNA, thusly promoting skipping of exon 9 in CFTR mRNA (Wang et al, 2004;Ayala et al, 2006;Buratti et al, 2008), suggesting its role in RNA splicing regulation. TDP-43 also can interact with many other splicing related protein Freibaum et al, 2010) via the C-terminal glycine-rich domain of the protein (Wang et al, 2004;Ayala et al, 2005).…”