Increased stability of mutant proteins may be responsible for neurodegenerative disease

The protein is TDP-43, which is involved in the manufacture of other proteins in the cell through its interaction with RNA. TDP-43 binds to RNA, and RNA is at the heart of the process by which the information in DNA is read and used for the manufacture of proteins. TDP-43 has been linked with a number of neurodegenerative diseases, including Alzheimer’s and Guam-Parkinson’s Dementia, and is therefore an important protein to study. In particular, mutations to TDP-43 are linked with Motor Neurone Disease and another neurodegenerative disease, Fronto-temporal Lobar Degeneration. Motor Neuron Disease in itself poses a cumulative lifetime risk of ~1 in 1000, which is comparable to that of Multiple Sclerosis.

Researchers at the University of Liverpool and the University of Nagoya in Japan have made the first studies of the molecular structure of some of these mutations and identified that they increase TDP-43 stability. This leads to the observed reduced rates of its degradation; a factor known to dictate the age at which Motor Neurone Disease sufferers first become aware of symptoms of the disease. The longer TDP-43 lingers in the cell, the earlier the sufferer’s age at which onset occurs.

Structural information was obtained using the SOLEIL beamlines SWING and DISCO which provided high quality small angle scattering data and Circular Dichroism data. Prof Hasnain added that these data were central to the paper. Data helped us to demonstrate that the increased half-life of the disease mutations in two TDP-43 nucleic acid binding domains arises from increased structural stability and resistance to aggregation."

These changes to TDP-43 are unusual because most proteins involved in neurodegeneration are unstable. This is the case in Alzheimer’s, Parkinson’s and Huntington’s diseases, and even Motor Neurone Disease that results from mutations in another protein, superoxide dismutase.

Lead authors James Austin and Dr Gareth Wright said:

“The fact that TDP-43 is associated with many neurodegenerative diseases warranted investigation. We were able to discover the protein’s structure, half-life, aggregation propensity and stability. We identified that TDP-43’s cellular longevity is due to higher thermal stability and resistance to unfolding.”  ‘Thermal stability’ here means that the protein is relatively stiff – it unfolds at a higher temperature than the un-mutated form (protein folding and unfolding is central to the way proteins interact with each other and other molecules). This has a knock-on effect that results in the accumulation of TDP-43 in the cell (the rates of its production and removal no longer match, as they must in a healthy cell). The authors argue that this ultimately leads to neurone death by changing the delicate metabolism of these fragile cells.

These findings open avenues for further research including development of drugs that decrease TDP-43 stability and accelerate its degradation. Professor Samar Hasnain and Dr Svetlana Antonyuk acknowledged the long-term support received from the MND Association.

The study is published in Proceedings of the National Academy of Science.