Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New gene mutations linked to ALS and nerve cell growth dysfunction

16.07.2012
NIH-supported research provides more complete picture of the disease

Researchers have linked newly discovered gene mutations to some cases of the progressive fatal neurological disease amyotrophic lateral sclerosis – ALS, also known as Lou Gehrig's disease. Shedding light on how ALS destroys the cells and leads to paralysis, the researchers found that mutations in this gene affect the structure and growth of nerve cells.

ALS attacks motor neurons, the nerve cells responsible for controlling muscles. People with ALS experience such early symptoms as limb weakness or swallowing difficulties. In most people, the disease leads to death three to five years after symptoms develop, usually as a result of respiratory failure.

Scientists at the University of Massachusetts Medical School, Worcester, collaborated with international ALS researchers to search for gene mutations in two large families with an inherited form of ALS. The researchers used a technique to decode only the protein-encoding portions of DNA, known as the exome, allowing an efficient yet thorough search of the DNA regions most likely to contain disease-causing mutations. This deep sequencing of the exome led to the identification of several different mutations in the gene for profilin (PFN1) which were present only in the family members that developed ALS. Further investigations of 272 other familial ALS cases across the world showed that profilin mutations were also found in a small subset (about 1 to 2 percent) of the familial ALS cases studied.

The protein profilin is a key part of the creation and remodeling of a nerve cell's scaffolding or cytoskeleton. In fly models, disrupting profilin stunts the growth of axons – the long cell projections used to relay signals from one neuron to the next or from motor neurons to muscle cells. After identifying the PFN1 mutations in ALS patients, the researchers demonstrated that these mutations inhibited axon growth in laboratory-grown motor neurons as well. They also found that mutant profilin accumulated in clumps in neural cells, as has been seen for other abnormal proteins associated with ALS, Parkinson's and Alzheimer's. Neural cells with PFN1 mutations also contained clumps of a protein known as TDP-43. Clumps of abnormal TDP-43 are found in most cases of ALS, further linking profilin to known ALS mechanisms.

John Landers, Ph.D., associate professor of neurology at the University of Massachusetts Medical School, described how studying ALS in large families is challenging. "ALS is a late-onset, rapidly progressive disease. Unless you've been following a family for decades, it is hard to get DNA samples to study," Dr. Landers said. "We were very fortunate to obtain the DNA samples with the help of our research collaborators and the affected families."

Over a dozen genes have been linked to ALS, and these findings support existing studies which suggest that cell cytoskeleton disruptions play a major role in ALS and other motor neuron diseases. Motor neurons are large cells with long axons that connect to muscle, and cytoskeleton proteins are especially important in the transport of proteins along the axon to the remote parts of the neuron. This information could be useful in developing strategies for detection and treatment of ALS.

"In all of the causative genes that we identify, we look for common pathways," Dr. Landers said. "Every time we are able to identify a new gene, we have another piece of the puzzle. Each one of these genes helps us to understand what's going on. The more of these we can find, the more we're going to know about what's going wrong in ALS."

Familial ALS accounts for 10 percent of all ALS cases, but the majority of ALS cases are sporadic, where the cause is unknown. Even though this new mutation is linked to familial ALS, it reveals information about the mechanisms underlying motor neuron degeneration in general, and also may have broader implications for understanding sporadic ALS.

"This discovery is highly significant and opens a new avenue of research," commented Amelie Gubitz, Ph.D., program director at the National Institute of Neurological Disorders and Stroke (NINDS), which funded the research. "There is growing evidence that ALS may be caused by a variety of cellular defects, and that it is a not a disorder with a single origin. Whether and where these disease pathways converge is an active area of research with important implications for therapy development."

This research was published online today by Nature. Scientists from research institutions in several countries contributed to the paper. In the United States, researchers from the University of Massachusetts Medical School, Emory University of Medicine, Atlanta, and Duke University School of Medicine, Durham, N. C., contributed to the study. In Italy, researchers from the University of Milan, the Institute of Hospitalization, Care and Scientific Research and the University of Pisa contributed to the study. In Israel, researchers from Tel Aviv Sourasky Medical Center contributed to the study. Additionally, researchers from the University Medical Centre Utrecht in the Netherlands, University of Guelph in Canada, and the Salpetriere Hospital in Paris contributed to the study.

The work was supported by grants from the NINDS, funded in part through the Recovery Act (NS065847, NS050557, NS070342). It was also supported by the Muscular Dystrophy Association, Agency of Research for Amyotrophic Lateral Sclerosis (AriSLA), SMA Europe, ALS Therapy Alliance, Project ALS, Partners in ALS Research, the Angel Fund, the Pierre L. de Bourgknecht ALS Research Foundation, the Al-Athel ALS Research Foundation, the ALS Family Charitable Foundation and a donation from Francesco Caleffi.

Reference: Wu, C-H., et al. "Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis" Nature, published online July 15, 2012.

For more information about ALS, visit: http://www.ninds.nih.gov/ALS

NINDS (http://www.ninds.nih.gov) is the nation's leading funder of research on the brain and nervous system. The NINDS mission is to reduce the burden of neurological disease – a burden borne by every age group, by every segment of society, by people all over the world.

About the National Institutes of Health (NIH): NIH, the nation's medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov.

NINDS press team | EurekAlert!
Further information:
http://www.nih.gov

More articles from Life Sciences:

nachricht Fine organic particles in the atmosphere are more often solid glass beads than liquid oil droplets
21.04.2017 | Max-Planck-Institut für Chemie

nachricht Study overturns seminal research about the developing nervous system
21.04.2017 | University of California - Los Angeles Health Sciences

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

Im Focus: Quantum-physical Model System

Computer-assisted methods aid Heidelberg physicists in reproducing experiment with ultracold atoms

Two researchers at Heidelberg University have developed a model system that enables a better understanding of the processes in a quantum-physical experiment...

Im Focus: Glacier bacteria’s contribution to carbon cycling

Glaciers might seem rather inhospitable environments. However, they are home to a diverse and vibrant microbial community. It’s becoming increasingly clear that they play a bigger role in the carbon cycle than previously thought.

A new study, now published in the journal Nature Geoscience, shows how microbial communities in melting glaciers contribute to the Earth’s carbon cycle, a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

New quantum liquid crystals may play role in future of computers

21.04.2017 | Physics and Astronomy

A promising target for kidney fibrosis

21.04.2017 | Health and Medicine

Light rays from a supernova bent by the curvature of space-time around a galaxy

21.04.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>