TDP43 (TAR DNA-binding protein 43): A key protein in ALS and FTLD, Parkinson's and Alzheimer's
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TAR DNA-binding protein 43 (TDP43) binds both DNA and RNA and has multiple functions in transcriptional repression, pre-mRNA splicing and translational regulation. It belongs to the hnRNP protein family and is highly expressed in many tissues including the brain, pancreas, placenta, lung, genital tract and endocrine tissues. Characterisation of transcriptome-wide binding sites shows that thousands of RNAs are bound by TDP43 in neurons.
TDP43 is predominantly located in the nucleus under normal physiological conditions, however it contains a nuclear localising signal (NLS) as well as a nuclear export signal (NES), which enables the shuttling of TDP43 between the nucleus and the cytosol. Under normal conditions, TDP43 interacts with mRNAs on which ribosomes are located separately, forming polysomes.
Various stresses can induce the clustering of ribosomes into a stalled state, resulting in the formation of stress granules (SG) containing TIA-1, G3BP, ataxin-2 and eIF4G1/2. In the stalled state, transcription is inhibited as a homeostatic response. Sustained stress and TDP43 misfolding creates aberrant SGs and pathogenic TDP43 aggregates.
Hyperphosphorylated, fragmented and ubiquitinated forms of TDP-43 have been identified as core components of cytosolic inclusions in sporadic ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration).
Misfolding and cytosolic mislocalisation of TDP43 also lead directly to a loss of normal TDP43 function, and the resultant disruption of protein and RNA homeostasis is considered another likely pathogenic mechanism in addition to the toxicity of inclusions.
As well as ALS (amyotrophic lateral sclerosis) and FTLD (frontotemporal lobar degeneration), mutations in TDP-43 have also been associated Parkinson's disease and Alzheimer's disease. Additionally TDP-43 regulates alternate splicing of the CFTR gene. The resulting aberrant splicing is associated with the pathological features typical of cystic fibrosis.
TDP43 is a key target protein in research around numerous neurodegenerative conditions.
Images courtesy of Dr Laura Ferraiuolo and Mr Marco Destro at the University of Sheffield
Recommended TDP43 related reading:
February 2019
April 2018
October 2016 Oligodendrocytes contribute to motor neuron death in ALS via SOD1 dependent mechanism
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