High-order secret decrypted for TDP-43 causing amyotrophic lateral sclerosis

7 Jun 2016. NUS scientists discovered a molecular mechanism which allows cellular processes to control the physiology and proteinopathy of TDP-43 whose aggregation is characteristic of amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and many other ageing-related human diseases.

Despite its first discovery in 1869, the ALS mechanism still remains a great mystery and there is no primary therapy. ALS occurs throughout the world regardless of race; and imposes a great burden on patients, their families and society. This was highlighted by the recent ALS Ice Bucket Challenge to promote awareness of the disease and to encourage donations to ALS research.

TDP-43 (TAR-DNA-binding protein-43) is composed of four domains. However, like all proteins involved in neurodegeneration, TDP-43 confounds scientists with its severe aggregation. TDP-43 inclusions are found in patients of about 97% ALS and about 45% FTD, as well as in Parkinson’s and Huntington’s diseases. Particularly, TDP-43 inclusion was recently revealed to amplify Alzheimer’s disease 10 times. Mysteriously, TDP-43 proteinopathies appear to propagate similarly to prion diseases, mostly mediated by its C-terminal prion-like domain, which also hosts almost all ALS-causing mutations. Previously, only two soluble RNA-binding domains have been extensively studied but the structures of the insoluble N-terminal and C-terminal prion-like domains remained unknown. In particular, whether the four domains interact with each other is completely unexplored due to the insolubility. Nevertheless, this piece of knowledge is extremely critical for understanding the physiology and proteinopathy of TDP-43 in cells.

A team led by Prof SONG Jianxing and his graduate students from the Department of Biological Sciences and NUS Graduate School for Integrative Sciences and Engineering in NUS recently determined structures and dynamics of both insoluble N-terminal domain and C-terminal prion-like domains. The study established that there is a fine balance between TDP-43’s normal function and its potential to cause neurodegeneration, thus supporting the emerging idea that protein aggregation in neurological disease may be an exaggeration of the normal functions of the aggregating proteins. Very recently, they further decoded the “high-order” secret for the first time: TDP-43 does have dynamic inter-domain interactions, which are coordinated by the intrinsically-disordered prion-like domain. Thus, TDP-43 appears to undergo conformational exchanges between “closed” and “open” states which are needed for its functions. The study thus offers a mechanism by which various cellular processes might control TDP-43 physiology and proteinopathy by mediating its inter-domain interactions.

With their discovery in 2005 that all previously-thought insoluble proteins could be solubilised in pure water, his team also deciphered that the driving forces for protein aggregation and interaction with membranes at least partly overlap, or are even two sides of the same coin. Their studies have been extensively highlighted by the international media.

Figure shows the TDP-43 inter-domain interaction holds high-order secrets for ALS/FTD pathogenesis. [Image credit: Song Jianxing]

References

1. Lim LZ, Wei Y, Lu Y, Song J. ALS-Causing Mutations Significantly Perturb the Self-Assembly and Interaction with Nucleic Acid of the Intrinsically Disordered Prion-Like Domain of TDP-43. PLoS Biol. 14 (2016) e1002338.

2. Qin H, Lim LZ, Wei Y, Song J. “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.

3. Song J. Insight into “insoluble proteins” with pure water. FEBS Lett. 583 (2009) 953.

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

5. Wei Y, Lim L, Wang L, Song J. Inter-domain interactions of TDP-43 as decoded by NMR. Biochem Biophys Res Commun. 16 (2016) 30476.