[Frontiers in Bioscience 13, 867-878, January 1, 2008]

Multiple roles of TDP-43 in gene expression, splicing regulation, and human disease

Emanuele Buratti1, Francisco E. Baralle1

1International Centre for Genetic Engineering and Biotechnology (ICGEB) 34012 Trieste, Italy


1. Abstract
2. Introduction
2.1. The TARDBP gene and its expression
2.2. The TDP-43 protein
2.3. TDP-43 cellular distribution
3. Functional roles of TDP-43 in transcriptional and splicing regulation
3.1. Transcriptional regulation
3.1.1. HIV-1 TAR DNA regulatory region
3.1.2. The mouse SP-10 gene promoter
3.2. Splicing regulation
3.2.1. CFTR exon 9
3.2.2. Apo AII Exon 3
3.3. mRNA stability
4. Involvement of TDP-43 in neurodegenerative disorders
5. Miscellaneous processes
6. Conclusions and perspectives


TDP-43 is a RNA/DNA binding protein that structurally resembles a typical hnRNP protein family member and displays a significant specificity for binding the common microsatellite region (GU/GT)n. Initially described as a regulator of HIV-1 gene expression, it has been reported in the past to affect both normal and pathological RNA splicing events. In particular, it has been shown to play a fundamental role in the occurrence of several monosymptomatic/full forms of Cystic Fibrosis caused by pathological skipping of CFTR exon 9 from the mature mRNA. Recently, and in a way probably unrelated to splicing, a hyperphosphorylated form of TDP-43 has also been found to accumulate in the cytoplasm of neuronal cells of patients affected by fronto temporal lobar degenerations. In addition to its role in transcription and splicing regulation, a growing body of evidence indirectly suggests that TDP-43 may be involved in other cellular processes such as microRNA biogenesis, apoptosis, and cell division. The aim of this work is to provide the basic facts about TDP-43 an assessment of the multiple functions ascribed to this protein.