Disease relevance of TARDBP

• To determine the function of TDP-43 in regulating HIV-1 gene expression, in vitro transcription analysis was performed [1].
• Cloning and characterization of a novel cellular protein, TDP-43, that binds to human immunodeficiency virus type 1 TAR DNA sequence motifs [1].
• In addition, transfection of a vector which expressed TDP-43 resulted in the repression of gene expression from an HIV-1 provirus [1].
• TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis [2].
• TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders [3].
• The finding of pathogenic mutations in TARDBP implicates TDP-43 as an active mediator of neurodegeneration in TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U [4].
• We have identified the specific cleavage site, Arg(208), of a pathological TDP-43 CTF purified from FTLD-U brains and show that the expression of this and other TDP-43 CTFs in cultured cells recapitulates key features of TDP-43 proteinopathy [5].
• Our work also suggests that decreasing the abundance of neurotoxic TDP-43 species, enhancing degradation or clearance of such TDP-43 derivatives and blocking the spread of the disease phenotype may have therapeutic potential for TDP-43 proteinopathies [6].

High impact information on TARDBP

• Nuclear factor TDP-43 and SR proteins promote in vitro and in vivo CFTR exon 9 skipping [7].
• Taken together, our results demonstrate that 5'-GTGTGT motifs on the complementary strand are required to prevent premature expression of SP-10 during spermatogenesis and implicate TDP-43 as the putative regulatory factor [8].
• Further, Northern analysis and immunohistochemistry of mouse testis showed the presence of TDP-43 in cell-types where the SP-10 gene remains repressed [8].
• TDP43 from C.elegans lacks the glycine-rich domain found at the carboxy terminus of the other two homologues [9].
• Notable among the proteins identified were the cytoskeletal cytokeratins, RNA helicases, oxidant-antioxidant enzymes, the TAR DNA binding protein (a protein that associates with nuclear domain 10 [ND10] structures), and heat shock protein 70- and 60-kDa isoforms (Hsp70 and Hsp60, respectively) [10].

Biological context of TARDBP

• Significantly, blocking of TDP-43 expression by small interfering RNA overrides the need for all the other cis-acting elements making exon 3 inclusion constitutive even in the presence of disrupted exonic and intronic enhancers [11].
• Although TDP-43 bound strongly to double-stranded TAR DNA via its ribonucleoprotein protein-binding motifs, it did not bind to TAR RNA extending from +1 to +80 [1].
• Nuclear factor TDP-43 binds to the polymorphic TG repeats in CFTR intron 8 and causes skipping of exon 9: a functional link with disease penetrance [12].
• We report that depletion of TDP43 through RNA interference removes splicing inhibition caused by unfavorable (UG)mU(n) sequences, indicating that TDP43 exerts a potent inhibitory effect in vivo [13].
• Dephosphorylation treatment of the sarkosyl insoluble fraction has shown that abnormal phosphorylation takes place in accumulated TDP-43 [2].

Anatomical context of TARDBP

• Furthermore, skein-like inclusions, neuronal intranuclear inclusions, and glial inclusions in the spinal cord of ALS patients are also positive for TDP-43 [2].
• Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord [3].

Psychiatry related information on TARDBP

• Despite significant clinical, genetic, and neuropathological heterogeneity of FTLD-U, TDP-43 is a common pathological substrate underlying a large subset of these disorders, thereby implicating TDP-43 in novel and unifying mechanisms of FTLD pathogenesis [14].

Associations of TARDBP with chemical compounds

• We identified a cDNA, designated TAR DNA-binding protein (TDP-43), which encodes a cellular factor of 43 kDa that binds specifically to pyrimidine-rich motifs in TAR [1].

Physical interactions of TARDBP

• We have also found that the (GU) repeats in the apoA-II context bind the splicing factor TDP-43 and interfere with exon 3 definition [11].
• We have recently identified nuclear factor TDP-43 as a novel splicing regulator capable of binding to this element in the CFTR pre-mRNA and inhibiting recognition of the neighboring exon [15].

Other interactions of TARDBP

• Depletion of TDP 43 overrides the need for exonic and intronic splicing enhancers in the human apoA-II gene [11].
• Overexpression of UBQLN recruited TDP-43 to detergent-resistant cytoplasmic aggregates that colocalized with the autophagosomal marker, LC3 [16].

Analytical, diagnostic and therapeutic context of TARDBP

• In this study we report the dissection of the RNA binding properties of TDP-43 and their functional implications in relationship with the splicing process [15].
• Antibody to TDP-43 was used in gel retardation assays to demonstrate that endogenous TDP-43, present in HeLa nuclear extract, also bound to TAR DNA [1].

References