Molecule find could pave way for new MND drugs

The molecule – called lipoamide – can prevent the formation of liquid droplet structures inside cells that are linked with motor neuron disease (MND), a fatal disease with few treatment options, researchers say. While the research is at an early stage, exploring ways of targeting this cell process could lead to new medicines to help prevent or reverse effects of the disease, the team says.

Investigating new treatments for MND is important, as most people die within two years of their diagnosis and none of the small number of approved medicines for the disease stop it from progressing, they add.

The findings were made by a large international team led by researchers from the University of Edinburgh and the Max Planck Institute of Molecular Cell Biology and Genetics.

They discovered lipoamide’s effects after screening 1,600 molecules to identify those affecting the formation of liquid droplets – known as stress granules – in cells.

Build-up of solid clumps of proteins inside stress granules – which normally only form briefly when cells are under stress – is one of the hallmarks of several neurodegenerative diseases, including MND.

They are promising targets for MND therapies as dozens of mutations in proteins bound up in the deposits are linked to disease-causing defects that arise in motor neurons, the team says.

Previous research suggested mutations in two proteins – known as FUS and TDP-43 – change how stress granules form and persist inside cells. This also stops the proteins from carrying out their key roles in repairing DNA and controlling how cells function.

Lab tests in fly and worm disease models, and on motor neurons derived from MND patients, showed that lipoamide can dissolve existing stress granules and prevent new ones from forming. Further analysis found lipoamide also improved cell health, neuron structure and motor function.

Unlike most drug molecules, lipoamide works by targeting floppy unstructured parts of proteins, needed to form stress granules, the team says.

While it is encouraging to have a new way of targeting MND-associated proteins, it remains unclear exactly why lipoamide has beneficial effects, the team says. More research is needed to understand whether this is an effective new way to combat the build-up of stress granules leading to MND, they add.

Dr Richard Wheeler, of the University of Edinburgh’s School of Biological Sciences, who led the study, said, “Identifying lipoamide powerfully demonstrates that drug-like molecules can target unstructured protein regions, with beneficial effects in experimental models of disease. Neurodegenerative diseases in people are often associated with unstructured proteins, making this an important demonstration of a potential new area for drug development.”

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