We have gone from finding a potential drug to identifying its target and mechanism-of-action.
- Delphine Larrieu
As well as offering a promising new way of treating the condition, known as Hutchinson-Gilford Progeria Syndrome (HGPS), the discovery could help in the development of drugs against cancer and other genetic diseases and might also suggest ways to alleviate diseases that we associate with normal ageing.
Around 150 people worldwide are known to suffer from HGPS, a disease which results from a specific genetic mutation which is not inherited. Usually diagnosed around the age of six months, children with HGPS lose their hair, look old and suffer many of the symptoms of ageing, including brittle bones, stroke and heart attacks. They generally live only until their early teens.
In cells from people with HGPS, the nucleus is marked out because, unlike a normal cell’s round nucleus, HGPS cell nuclei are drastically misshapen. Scientists believe this makes the cells more fragile, contributing to HGPS patients’ symptoms.
Proteins called Lamin A and Lamin C play a vital role in nuclear architecture, acting as ‘scaffolding’ for the nucleus. In HGPS, however, mutations in the gene that makes these proteins mean they cannot shape the nucleus correctly.
Working with cells from HGPS patients, researchers from the Wellcome Trust/CRUK Gurdon Institute at the University of Cambridge and the CNRS in France scoured the scientific literature for compounds that might affect nuclear architecture. They then tested a shortlist of the most promising compounds on the cells in the laboratory. Their results are published in the journal Science.
They found that one compound – which they were able to improve, yielding a molecule that they have named Remodelin – effectively improved the damaged nuclei, restoring their shape. Further tests revealed that doing so also improved the health of the cells, making them grow and divide more normally.
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Image: Cell nucleus before (left) and after (right) treatment with Remodelin
Credit: Delphine Larrieu
Reproduced courtesy of the University of Cambridge
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