An ALS-causing protein with two faces

12 Feb 2015 Scientists discovered that a proteininvolved in neurodegeneration reveals two faced amino-ends.

TDP-43, like all proteins involved in neurodegeneration, confounds structural biologists with its severe aggregation. TDP-43 inclusions are found in patients of about 97% Amyotrophic lateral sclerosis (ALS) and about 45% Frontotemporal dementia (FTD), as well as Parkinson’s and Huntington’s diseases. Particularly, TDP-43 inclusion was revealed to amplify Alzheimer's disease 10 times.

Mysteriously, the TDP-43 N-terminus acts as a double-edged sword for both physiology and proteinopathy, but its molecular mechanism remained unknown due to aggregation.

A team led by Prof SONG Jianxing from the Department of Biological Sciences in NUS has discovered that so far all insoluble proteins tested can be dissolved in pure water and deciphered that the TDP-43 N-terminus encodes a novel ubiquitin-like fold and that its unfolded form in equilibrium can be mediated by directly binding to nucleic acids.

Despite its first description in 1869, the ALS mechanism still remains a great mystery and there is no primary therapy. ALS occurs throughout the world and imposes a great burden on patients, patients’ family and society, as highlighted by the recent ice bucket challenge.

The results provide a molecular mechanism rationalizing the functional dichotomy of TDP-43 and also shed light on the formation and dynamics of cellular ribonucleoprotein granules, which have been recently linked to ALS pathogenesis. The study also suggests a therapeutic strategy for treating TDP-43-causing neurodegenerative diseases by stabilizing the N-terminus with nucleic acids or designed molecules.

His team is currently focused on testing the strategy to reducing TDP-43 toxicity by stabilizing its N-terminus. An academic community focused on neurodegenerative diseases has interviewed Prof Song and other experts worldwide in the relevant fields and published a story on this breakthrough: http://www.alzforum.org/news/research-news/tdp-43-structure-reveals-two-faced-amino-end

 

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The image shows TDP-43 N-terminus encodes a novel ubiquitin-like fold (A), which is the first capable of directly binding nucleic acids; and its unfolded form (B) in equilibrium with an exchange rate of 14 Hz. The well-folded ubiquitin-like fold is needed for the physiological functions (C), while the unfolded form will aggregate in vivo, which is a histological hallmark of about 97% ALS and 45% FTD, as well as many other neurodegenerative diseases (D). [Image credit: Song Jianxing]

 

References

1. Qin H, Lim LZ, Wei Y, Song JX. “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. 111 (2014) 18619.

2. Song JX. “Why do proteins aggregate?”Intrinsically insoluble proteins" and "dark mediators" revealed by studies on "insoluble proteins" solubilized in pure water”. F1000Res. 2 (2013) 94.