Protein's hydrogen bond linked to motor neuron disease

It is suspected that several neurodegenerative diseases are caused by the build up of certain proteins in the brain after they lose the ability to fold properly and clump together. In a study published in the Proceedings of the National Academy of Sciences¹ a team of biochemists has pinned down how improper protein folding leads to the motor neuron disease amyotrophic lateral sclerosis (ALS), better known as Lou Gehrig's disease.

The superoxide dismutase 1 enzyme, or SOD1, is present in all organisms. The enzyme captures copper – which would be toxic to cells if left to roam free — and then uses the bound copper to scavenge harmful oxygen radicals.

SOD1 typically unfolds and re-folds spontaneously, without usually causing health problems. However, in some ALS sufferers, it somehow unfolds and become entangled.

"It is like an avalanche effect that spreads rapidly through the spinal cord causing progressive paralysis of the muscles," says Mikael Oliveberg, a biophysicist at Stockholm University and co-author of the paper.

The research team, including Wael Awad, a crystallographer at Cairo University used a combination of protein engineering, nuclear magnetic resonance and crystallography to pinpoint how this effect occurs.

They found that the enzyme has a peculiar hydrogen bond running through its core that makes it dynamic and "floppy". Under normal circumstances, when the enzyme binds copper, it stabilizes the folded configuration, making the structure more rigid.

"The fully unfolded protein stands out as the prime suspect for pathological aggregation in ALS," says Oliveberg, adding that looking for ways to selectively stabilize the enzyme is "a promising pharmaceutical strategy."

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