Old drug could help treat motor neurone disease

An international study led by biochemists at the University of Liverpool has shown that the drug molecule ebselen can correct many of the toxic characteristics of a protein that causes some cases of hereditary motor neurone disease.

Motor neurone disease is an incurable, progressive disease that attacks the nerves controlling movement so muscles no longer work. It affects about five thousand people in the UK at any one time and present treatment options have only a modest effect in improving quality of life.

Inherited motor neurone disease is a rare form of the disease (5-10% of total cases) that runs in families. Around 20% of hereditary motor neurone disease cases are caused by mutations in a gene which codes for a protein called SOD1. When the SOD1 gene is mutated, the protein assembly process malfunctions and steps are missed out. This makes the SOD1 protein structurally unstable leading to formation of protein “clumps” in the motor neurones, causing them to die.

In a study, published in Nature Communications, scientists from the University of Liverpool, University of Florence and University of Wollongong used state of the art crystallography, mass spectrometry and in-cell NMR technologies to search for a drug molecule which could “correct” the SOD1 assembly line.

The University of Liverpools reports they found ebselen, a drug which was discovered in the eighties and has been investigated as a potential treatment for a variety of nervous system disorders, can effectively restore several important steps in the SOD1 assembly process including folding, dimerisation and zinc binding.

Dr Gareth Wright, an motor neurone disease researcher at the University of Liverpool, said “This discovery has the potential to prevent the accumulation of SOD1 into the large aggregates we see within the motor neurons of effected individuals. If we can stop that, we might be able to stop the neurons dying.”

Professor Samar Hasnain, a structural biologist at the University of Liverpool, said “The next step is to test ebselen in settings more accurately resembling human neuronal cells and optimising it so that it can become useful as a drug for motor neuron disease.”

The work received funding from the Motor Neurone Disease Association.

Commenting on the study, Dr Brian Dickie, Director of Research Development at the Motor Neurone Disease Association, said “A causal link between the SOD1 gene and certain forms of hereditary motor neuron disease was established a quarter of a century ago. It is very encouraging to see new therapeutic strategies starting to emerge from the considerable advances in scientific understanding that have occurred in recent years.”

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