A team of scientists, including faculty at the University of Massachusetts Medical School (UMMS), have discovered a gene that influences survival time in amyotrophic lateral sclerosis (ALS, also known as Lou Gehrig's disease).
The study, published today in Nature Medicine, describes how the loss of activity of a receptor called EphA4 substantially extends the lifespan of people with the disease. When coupled with a UMMS study published last month in Nature identifying a new ALS gene (profilin-1) that also works in conjunction with EphA4, these findings point to a new molecular pathway in neurons that is directly related to ALS susceptibility and severity.
"Taken together, these findings are particularly exciting because they suggest that suppression of EphA4 may be a new way to treat ALS," said Robert Brown, MD, DPhil, a co-author on the study and chair of neurology at UMass Medical School.
ALS is a progressive, neurodegenerative disorder affecting the motor neurons in the central nervous system. As motor neurons die, the brain's ability to send signals to the body's muscles is compromised. This leads to loss of voluntary muscle movement, paralysis and eventually respiratory failure. The cause of most cases of ALS is not known. Approximately 10 percent of cases are inherited. Though investigators at UMMS and elsewhere have identified several genes shown to cause inherited or familial ALS, almost 50 percent of these cases have an unknown genetic cause. There are no significant treatments for the disease.
Wim Robberecht, MD, PhD, lead investigator of the Nature Medicine study and a researcher at the University of Leuven in Belgium and the Vesalius Research Center, screened for genes in zebrafish that blunt the adverse effect of the ALS mutant gene SOD1. Through this process, his team identified EphA4 as an ALS modifier. Dr. Robberecht's team went on to show that when this gene is inactivated in mice with ALS, the mice live longer.
Dr. Robberecht then turned to UMass Medical School to confirm that turning off EphA4 in human ALS cells would slow the progression of the disease. Dr. Brown and his team identified two human ALS cases with mutations in the EphA4 gene which, like the zebrafish and the mice, had unusually long survival times. This suggests that blocking EphA4 in patients with ALS may be a potential therapeutic target in the future.
In an exciting, related development, a new ALS gene (profilin-1) identified last month by UMMS scientists works in conjunction with EphA4 in neurons to control outgrowth of motor nerve terminals. In effect, gene variants at both the top and the bottom of the same signaling pathway are shown to effect ALS progression. Together these discoveries highlight a new molecular pathway in neurons that is directly related to ALS susceptibility and severity and suggests that other components of the pathway may be implicated in ALS."It is exciting that these two studies identify the same pathway in ALS," said John Landers, PhD, associate professor of neurology and lead author of the PFN1 study. "Hopefully this discovery will accelerate efforts to finding a treatment for ALS."
Forthcoming Nature Medicine Paper: Van Hoecke A, Schoonaert L, Lemmens R, Timmers M, Staats KA, Laird AS, Peeters E, Philips T, Goris A, Dubois B, Andersen P, Al-Chalabi A, Thijs V, Turnley AM, van Vught PW, Veldink JH, Van Den Bosch L, Gonzalez-Perez P, Van Damme P, Brown RH Jr, van den Berg LH, Robberecht W. Genetic screening in zebrafish identifies EphA4 of the ephrin axonal repellent system as a disease modifier of amyotrophic lateral sclerosis in rodent models and patients. In press, Nat Medicine.
Profilin1 Paper: Wu C-H, Fallini C, Ticozzi N, Keagle PJ, Sapp PC, Piotrowska K, Lowe P, Koppers M, McKenna-Yasek D, Baron D, Kost E, Gonzalez-Perez P, Fox AD, Adams J, Taroni F, Tiloca C, Leclerc AL, Chafe SC, Mangroo D, Moore MJ, Zitzewitz J, Xu Z-S, van den Berg LH, Glass JD, Siciliano G, Cirulli ET, Goldstein DB, Salachas F, Meninger V, Rossoll W, Ratti A, Gellera C, Bosco DA, Bassell GJ, Silani V, Drory VE, Brown RH Jr., Landers JE. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature. 2012 Jul 15
Jim Fessenden | EurekAlert!
Symbiotic bacteria: from hitchhiker to beetle bodyguard
28.04.2017 | Johannes Gutenberg-Universität Mainz
Nose2Brain – Better Therapy for Multiple Sclerosis
28.04.2017 | Fraunhofer-Institut für Grenzflächen- und Bioverfahrenstechnik IGB
More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.
Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...
Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.
"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...
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...
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...
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...
28.04.2017 | Event News
20.04.2017 | Event News
18.04.2017 | Event News
28.04.2017 | Medical Engineering
28.04.2017 | Earth Sciences
28.04.2017 | Life Sciences