Amyotrophic lateral sclerosis (ALS) mediated by protein dynamics and interaction with membranes
15 Feb 2016 NUS scientists discovered that the dynamics of an “insoluble” protein and its interaction with membranes hold clues for the mechanism and progression of ALS.
Despite its first description in 1869, the ALS mechanism still remains a mystery and there is no primary therapy. ALS occurs throughout the world and imposes a great burden on patients, their families and society, as highlighted by the recent ALS Ice Bucket Challenge to promote awareness of the ALS disease (also known as Lou Gehrig's Disease); and to encourage donations to ALS research.
TDP-43 (TAR-DNA-binding protein-43), like all proteins involved in neurodegeneration, confounds scientists with its severe aggregation. TDP-43 inclusions are found in patients of about 97% ALS and about 45% Frontotemporal dementia (FTD), as well as 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.
A team led by Prof SONG Jianxing from the Department of Biological Sciences in NUS deciphered that despite being intrinsically disordered, the assembly of the TDP-43 prion-like domain is extremely specific. An ALS-causing point mutation even like M337V is sufficient to remodel the energy landscape to favour the formation of irreversible aggregates or/and amyloid oligomers. Surprisingly, they also decoded that the TDP-43 prion-like domain contains a membrane-interacting subdomain. “This interaction with the membrane is perhaps the most novel aspect of the work,” commented Jim SHORTER, University of Pennsylvania, Philadelphia. Previously, Prof Song’s group also decrypted that TDP-43 N-terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium that can be mediated by directly binding to nucleic acids.
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. Furthermore, the membrane-association mechanism may represent a future avenue of research for the physiological functions and pathological roles of TDP-43, as well as other aggregation-prone proteins such as VAPB (vesicle-associated membrane protein-associated protein B) and SOD1 (superoxide dismutase 1) mutantspreviously revealed by Prof Song’s group.
His team is currently focused on establishing the membrane-interaction as a common mechanism for aggregation-prone proteins to trigger human diseases and aging. Their unique studies on “insoluble” proteins suggest that the driving forces for protein aggregation and interaction with membranes are at least partly overlapped, or even two sides of the same coin. Their studies have been extensively highlighted by the international media. The academic community focused on neurodegenerative diseases has interviewed Prof Song and other experts worldwide in the relevant fields and published a detailed story on the breakthroughs: How TDP-43’s Dishevelled Tail Spells Trouble: http://www.alzforum.org/news/research-news/how-tdp-43s-disheveled-tail-spells-trouble
(A) The self-assembly energy landscape of the TDP-43 prion-like domain can be globally remodelled by a large set of ALS-causing mutations to trigger human neurodegenerative diseases. (B) The domain organisation of TDP-43. (C) TDP-43 N-terminus encodes a novel ubiquitin-like fold and its unfolded form in equilibrium with an exchange rate constant of 14 Hz. [Image credit: Song Jianxing]
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. Qin H, Lim L, Wei Y, Gupta G, Song J. Resolving the paradox for protein aggregation diseases: NMR structure and dynamics of the membrane-embedded P56S-MSP causing ALS imply a common mechanism for aggregation-prone proteins to attack membranes. F1000Res. (2013) v2. eCollection.
6. Lim L, Lee X, Song J. Mechanism for transforming cytosolic SOD1 into integral membrane proteins of organelles by ALS-causing mutations. Biochim Biophys Acta (Biomembranes). 1848 (2014) 1.