TDP-43 is a transcriptional repressor that binds to chromosomally integrated TAR DNA and represses HIV-1 transcription. In addition, this protein regulates alternate splicing of the CFTR gene. In particular, TDP-43 is a splicing factor binding to the intron8/exon9 junction of the CFTR gene and to the intron2/exon3 region of the apoA-II gene.[2] A similar pseudogene is present on chromosome 20.[3]
TDP-43 has been shown to bind both DNA and RNA and have multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. Recent work has characterized the transcriptome-wide binding sites revealing that thousands of RNAs are bound by TDP-43 in neurons.[4]
TDP-43 was originally identified as a transcriptional repressor that binds to chromosomally integrated trans-activation response element (TAR) DNA and represses HIV-1 transcription.[1] It was also reported to regulate alternate splicing of the CFTR gene and the apoA-II gene.
In spinal motor neurons TDP-43 has also been shown in humans to be a low molecular weight neurofilament (hNFL) mRNA-binding protein.[5] It has also shown to be a neuronal activity response factor in the dendrites of hippocampal neurons suggesting possible roles in regulating mRNA stability, transport and local translation in neurons.[6]
Recently, it has been demonstrated that zinc ions are able to induce aggregation of endogenous TDP-43 in cells.[7] Moreover, zinc could bind to RNA binding domain of TDP-43 and induce the formation of amyloid-like aggregates in vitro.[8]
HIV-1, the causative agent of acquired immunodeficiency syndrome (AIDS), contains an RNAgenome that produces a chromosomally integrated DNA during the replicative cycle. Activation of HIV-1 gene expression by the transactivator "Tat" is dependent on an RNA regulatory element (TAR) located "downstream" (i.e. to-be transcribed at a later point in time) of the transcription initiation site.
Mutations in the TARDBP gene are associated with neurodegenerative disorders including frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS).[14] In particular, the TDP-43 mutants M337V and Q331K are being studied for their roles in ALS.[15][16] Cytoplasmic TDP-43 pathology is the dominant histopathological feature of multisystem proteinopathy.[17] The N-terminal domain, which contributes importantly to the aggregation of the C-terminal region, has a novel structure with two negatively charged loops.[18]
↑Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C (June 2007). "TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein". Molecular and Cellular Neurosciences. 35 (2): 320–7. doi:10.1016/j.mcn.2007.03.007. PMID17481916.
↑Wang IF, Wu LS, Chang HY, Shen CK (May 2008). "TDP-43, the signature protein of FTLD-U, is a neuronal activity-responsive factor". Journal of Neurochemistry. 105 (3): 797–806. doi:10.1111/j.1471-4159.2007.05190.x. PMID18088371.
↑Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ (July 2007). "TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease". Acta Neuropathologica. 114 (1): 63–70. doi:10.1007/s00401-007-0226-5. PMID17492294.
↑Sreedharan J, Blair IP, Tripathi VB, Hu X, Vance C, Rogelj B, Ackerley S, Durnall JC, Williams KL, Buratti E, Baralle F, de Belleroche J, Mitchell JD, Leigh PN, Al-Chalabi A, Miller CC, Nicholson G, Shaw CE (March 2008). "TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis". Science. 319 (5870): 1668–72. doi:10.1126/science.1154584. PMID18309045.
↑Kim HJ, Kim NC, Wang YD, Scarborough EA, Moore J, Diaz Z, MacLea KS, Freibaum B, Li S, Molliex A, Kanagaraj AP, Carter R, Boylan KB, Wojtas AM, Rademakers R, Pinkus JL, Greenberg SA, Trojanowski JQ, Traynor BJ, Smith BN, Topp S, Gkazi AS, Miller J, Shaw CE, Kottlors M, Kirschner J, Pestronk A, Li YR, Ford AF, Gitler AD, Benatar M, King OD, Kimonis VE, Ross ED, Weihl CC, Shorter J, Taylor JP (March 2013). "Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS". Nature. 495 (7442): 467–73. doi:10.1038/nature11922. PMC3756911. PMID23455423.
Kwong LK, Neumann M, Sampathu DM, Lee VM, Trojanowski JQ (July 2007). "TDP-43 proteinopathy: the neuropathology underlying major forms of sporadic and familial frontotemporal lobar degeneration and motor neuron disease". Acta Neuropathologica. 114 (1): 63–70. doi:10.1007/s00401-007-0226-5. PMID17492294.
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Buratti E, Baralle FE (September 2001). "Characterization and functional implications of the RNA binding properties of nuclear factor TDP-43, a novel splicing regulator of CFTR exon 9". The Journal of Biological Chemistry. 276 (39): 36337–43. doi:10.1074/jbc.M104236200. PMID11470789.
Buratti E, Brindisi A, Giombi M, Tisminetzky S, Ayala YM, Baralle FE (November 2005). "TDP-43 binds heterogeneous nuclear ribonucleoprotein A/B through its C-terminal tail: an important region for the inhibition of cystic fibrosis transmembrane conductance regulator exon 9 splicing". The Journal of Biological Chemistry. 280 (45): 37572–84. doi:10.1074/jbc.M505557200. PMID16157593.
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