Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Blocking a premature aging syndrome with anticancer drugs

30.08.2005


A class of anticancer drugs currently being evaluated in phase 3 clinical trials may also be an effective treatment for Hutchinson-Gilford progeria syndrome (HGPS), a fatal genetic disorder that causes premature aging. If upcoming studies in a HGPS mouse model validate the results of experiments in cultured cells in the laboratory, a clinical trial of these drugs in HGPS children may begin as early as next spring.



Brian Capell, a New York University medical student participating in the Howard Hughes Medical Institute/National Institutes of Health Research Scholars Program and the first author of the study, reported the findings in the August 29, 2005, issue of the Proceedings of the National Academy of Sciences. The HHMI-NIH Research Scholars Program gives outstanding medical and dental students the opportunity to conduct biomedical research under the direct mentorship of senior NIH research scientists.

Although HGPS is a rare disease that affects only one child in 4 million, the disease has received wide publicity due to its striking nature. Children born with HGPS appear normal, but they experience growth retardation and show symptoms of accelerated aging -- namely hair loss, skin wrinkling, and fat loss -- around the first year of age. Accelerated cardiovascular disease also ensues, which typically causes death around age 12.


In 2003, researchers in Francis Collins’s lab at the National Human Genome Research Institute discovered that mutations in the lamin A (LMNA) gene cause HGPS. The discovery has prompted renewed interest among researchers to study this rare syndrome.

When Capell entered Collins’s lab in July 2004, he immediately set his sights on understanding the molecular basis of HGPS. "What really interested me in this research in the first place were the potential links to aging and atherosclerotic disease," says Capell. Indeed, understanding HGPS at the molecular level may illuminate general processes involved normal human aging.

The LMNA mutation implicated in HGPS causes an internal stretch of 50 amino acids within the encoded lamin A protein to be deleted. This mutated protein is called "progerin." Lamin A normally constitutes a major component of the scaffold-like network of proteins just inside the nuclear membrane called the lamina. When mutated to progerin, however, lamin A fails to integrate properly into the lamina, thereby disrupting the nuclear scaffolding and causing gross disfigurement of the nucleus. Cells with progerin have a nucleus with a characteristic "blebbed," or lobular, shape.

To find its way to the lamina, lamin A carries two tags, rather like zip codes, that help to direct its travels. One tag at the end of lamin A instructs another protein to modify it through a process called farnesylation. Farnesylation tethers lamin A to the inner nuclear membrane. Once there, a second tag within the protein signals an enzyme to cleave off the terminal portion of the protein, including the farnesyl group, freeing lamin A to integrate properly into the nuclear lamina.

Because progerin carries the farnesylation tag but lacks the second cleavage tag, Capell speculated that progerin was becoming permanently stuck to the inner nuclear membrane. There, he suspected, it enmeshed other scaffolding proteins, preventing their proper integration into the lamina. If progerin’s sticking to the inner nuclear membrane is indeed the culprit in nuclear blebbing and the root of the HGPS defect, Capell reasoned that he could prevent these defects by blocking farnesylation of progerin.

Capell’s hunch proved correct. When he changed one amino acid within progerin’s farnesylation tag to prevent the addition of a farnesyl group and tested the effect in cells grown in the laboratory, progerin did not anchor itself to the inner nuclear membrane and instead clumped within the nucleus. Moreover, Capell observed no nuclear blebbing.

Capell then tried treating the cells carrying progerin with farnesyltransferase inhibitors (FTIs), drugs originally developed to inhibit certain cancer-causing proteins that require farnesylation for function, like the famous oncoprotein Ras, which are now being tested in phase III clinical trials of patients with myeloid leukemia. Again, he witnessed no blebbing. More importantly, he saw the same effect when he treated cells grown from skin biopsies of HGPS patients: HGPS cell blebbing decreased to near normal levels.

"FTIs, originally developed for cancer, are capable of reversing the dramatic nuclear structure abnormalities that are the hallmark of cells from children with progeria. This is a stunning surprise, rather like finding out that the key to your house also works in the ignition of your car," says Collins, the principal investigator.

Capell’s work on progerin has so inspired him that he has decided to spend another year in Collins’s lab, with his next task being to test the effects of FTIs in their mouse model of HGPS.

Jennifer Donovan | EurekAlert!
Further information:
http://www.hhmi.org

More articles from Life Sciences:

nachricht Rutgers scientists discover 'Legos of life'
23.01.2018 | Rutgers University

nachricht Researchers identify a protein that keeps metastatic breast cancer cells dormant
23.01.2018 | Institute for Research in Biomedicine (IRB Barcelona)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Optical Nanoscope Allows Imaging of Quantum Dots

Physicists have developed a technique based on optical microscopy that can be used to create images of atoms on the nanoscale. In particular, the new method allows the imaging of quantum dots in a semiconductor chip. Together with colleagues from the University of Bochum, scientists from the University of Basel’s Department of Physics and the Swiss Nanoscience Institute reported the findings in the journal Nature Photonics.

Microscopes allow us to see structures that are otherwise invisible to the human eye. However, conventional optical microscopes cannot be used to image...

Im Focus: Artificial agent designs quantum experiments

On the way to an intelligent laboratory, physicists from Innsbruck and Vienna present an artificial agent that autonomously designs quantum experiments. In initial experiments, the system has independently (re)discovered experimental techniques that are nowadays standard in modern quantum optical laboratories. This shows how machines could play a more creative role in research in the future.

We carry smartphones in our pockets, the streets are dotted with semi-autonomous cars, but in the research laboratory experiments are still being designed by...

Im Focus: Scientists decipher key principle behind reaction of metalloenzymes

So-called pre-distorted states accelerate photochemical reactions too

What enables electrons to be transferred swiftly, for example during photosynthesis? An interdisciplinary team of researchers has worked out the details of how...

Im Focus: The first precise measurement of a single molecule's effective charge

For the first time, scientists have precisely measured the effective electrical charge of a single molecule in solution. This fundamental insight of an SNSF Professor could also pave the way for future medical diagnostics.

Electrical charge is one of the key properties that allows molecules to interact. Life itself depends on this phenomenon: many biological processes involve...

Im Focus: Paradigm shift in Paris: Encouraging an holistic view of laser machining

At the JEC World Composite Show in Paris in March 2018, the Fraunhofer Institute for Laser Technology ILT will be focusing on the latest trends and innovations in laser machining of composites. Among other things, researchers at the booth shared with the Aachen Center for Integrative Lightweight Production (AZL) will demonstrate how lasers can be used for joining, structuring, cutting and drilling composite materials.

No other industry has attracted as much public attention to composite materials as the automotive industry, which along with the aerospace industry is a driver...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

10th International Symposium: “Advanced Battery Power – Kraftwerk Batterie” Münster, 10-11 April 2018

08.01.2018 | Event News

See, understand and experience the work of the future

11.12.2017 | Event News

Innovative strategies to tackle parasitic worms

08.12.2017 | Event News

 
Latest News

Rutgers scientists discover 'Legos of life'

23.01.2018 | Life Sciences

Seabed mining could destroy ecosystems

23.01.2018 | Earth Sciences

Transportable laser

23.01.2018 | Physics and Astronomy

VideoLinks Science & Research
Overview of more VideoLinks >>>