. TDP-43 N terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be shifted by binding to ssDNA. Proc Natl Acad Sci U S A. 2014 Dec 30;111(52):18619-24. Epub 2014 Dec 12 PubMed.


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  1. This work by Qin and colleagues is a step toward understanding the molecular mechanisms involved in TDP-43 pathology. These results, when seen in conjunction with the recently described role of TDP-43 amino terminus region in aggregation processes that lead to TDP 43 loss of function (Budini et al., 2014), show how important the N-terminal domain is to the overall picture of ALS and FTLD pathogenesis.

    Qin et al. have found that the N-terminal region of TDP-43 has a folded structure and an unfolded structure that co-exist in a tightly regulated equilibrium that depends on salt and protein concentration. This equilibrium also might be affected by intra- and intermolecular interactions. The well-folded conformation appears to assume a ubiquitin-like structure able to bind ssDNA and RNA molecules. This conformation allows TDP-43 to form oligomers, shifting the equilibrium toward the folded conformation.

    These results shed light on two of the most studied features of pathogenic TDP-43—protein aggregation and loss of function. The mechanisms behind these events are poorly understood and it is still unknown if the aggregation is a cause or a consequence of the disease. The existence of an equilibrium between folded and unfolded conformations of the protein in vivo could explain several observations. For instance, in some patients affected by ALS and FTLD, increased TDP-43 levels have been found, an aspect that correlates well with the possible disturbance of the equilibrium between the folded and the unfolded states.

    In pathological conditions, TDP-43 loses some of its functions. The unfolded N-terminal domain of TDP-43 may favor aggregation and at the same time hamper the stabilization of the nucleic acids at the RNA recognition motifs of the protein, leading to the impairment of TDP-43 function.

    However, it remains to be seen if some other events trigger the shift of this balance. For example, environmental stress could stabilize the unfolded form. Whatever shifts the equilibrium to the unfolded structure, it will be important to understand if it is possible to intervene in the aggregation process and bring the protein back to the well-folded state, because this may prevent or repair the neuronal damage. Hence these results open new frontiers towards novel therapeutic strategies in order to prevent irreversible protein aggregation and neuronal death.


    . TDP-43 loss of cellular function through aggregation requires additional structural determinants beyond its C-terminal Q/N prion-like domain. Hum Mol Genet. 2015 Jan 1;24(1):9-20. Epub 2014 Aug 13 PubMed.

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  1. TDP-43 Structure Reveals Two-Faced Amino End