The progeria-diseased cell nucleus (left) is deformed compared with a normal cell nucleus (right) because it has higher levels of progerin. Blue is DNA and red is progerin.
Image credit: K. Djabali / TUM.
Progeria - short for Hutchinson-Gilford progeria syndrome - is an extremely rare and fatal genetic disorder where children appear to age prematurely because of a faulty protein in their cell nuclei. As the defective protein - known as progerin - accumulates, it interferes with a number of cell functions.
In the journal Aging Cell, researchers from the Technical University at Munich (TUM) in Germany, describe how they succeeded in reducing levels of progerin in diseased cells by reactivating a protein-clearing process. They did this using sulforaphane - an antioxidant found in broccoli and other cruciferous vegetables, such as cabbage and Brussels sprouts.
For their study, the team - led by Karima Djabali, a professor in the TUM School of Medicine and the Institute for Medical Engineering - compared progeria-diseased cells with healthy cells to look for differences in the proteins in the cell nuclei.
Most progeria patients carry a faulty gene that produces a faulty version of a protein called lamin A. This faulty version is what is known as progerin.
Normal lamin A is an important component of the matrix that surrounds DNA in the cell nucleus and plays a key role in gene expression. But the progerin version of lamin A does not have a function; it just becomes a nuisance as it accumulates because the cell continues to make it as instructed by the faulty gene.
However, as it collects in the nucleus, progerin causes the cell to "age," meaning patients with the disease develop classic health problems of old age, such as atherosclerosis, osteoporosis, stroke and heart attack.
Using sophisticated protein analysis techniques - known as proteomics - the team compared the diseased and normal cells and found a surprising similarity.
Healthy cells also produce progerin, but they eliminate it quickly
The healthy cells also contained progerin - but at much lower levels. It seems that progerin is a natural byproduct in cells, but healthy cells get rid of it before it can accumulate to dangerous levels, as Prof. Djabali explains:
"Progerin is also produced in healthy cells, probably as a byproduct. A well-functioning cellular waste disposal system can break down these small quantities of progerin."
One of the main differences between the healthy and diseased cells was that levels of progerin in the nuclei of diseased cells were 10-20 times higher than levels in the nuclei of healthy cells. Thus, the nuclei of progeria-diseased cells appear to have a huge backlog of cell debris that is not removed.
On further investigation, the team also found that the mechanism that removes debris from the cell nucleus - known as ubiquitin-proteasome system and autophagy - did not work properly in the progeria-diseased cells.
These debris-clearing systems comprise huge complexes of proteins that do not appear to be produced in sufficient quantities in progeria-diseased cells.
Prof. Djabali says:
"These errors in the cellular debris disposal system enhance the effect that progerin accumulates and causes cell damage within a short time."
Altogether, the team found the progeria-diseased cell nuclei had over 28 proteins - each carrying out a number of cell functions - with faults in them, and all the faults came from the same mutation of the lamin A gene.
Sulforaphane reactivated protein and debris elimination in the cell nuclei
In the second part of the study, the team searched the literature for substances that might activate the debris-clearing system in the cell nuclei and help rid the diseased cells of excess progerin.
That is how they found the antioxidant sulforaphane - a substance present in broccoli and other members of the crucifer family - that activates debris elimination in cells.
When the researchers treated progeria-diseased cells with sulforaphane, they found it significantly reduced levels of progerin in their nuclei. Diseased cells treated with sulforaphane also appeared to have less DNA damage and nuclear deformations, they note.
Prof. Djabali warns that it is early days and their experiments were "very basic," but the study is a step toward developing an effective treatment for progeria, and it may also "help us develop anti-aging strategies in the future," she adds.
In May 2013, Medical News Today learned of a study that suggested accumulated progerin may also have another damaging effect in cells to contribute to progeria disease; it stops large proteins from entering the nucleus.