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 reports about: > DNA > DNA samples > Gates Foundation > Massachusetts > Medical Wellness > NIH > NINDS > Nature Immunology > Neurological Disorder > PFN1 > familial ALS > gene mutation > health services > lateral sclerosis > medical research > motor neuron disease > nerve cell > neurological disease
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences