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!
Sweetening neurotransmitter receptors and other neuronal proteins
28.10.2016 | Max-Planck-Institut für Hirnforschung
A new look at thyroid diseases
28.10.2016 | Jacobs University Bremen gGmbH
Ultrafast lasers have introduced new possibilities in engraving ultrafine structures, and scientists are now also investigating how to use them to etch microstructures into thin glass. There are possible applications in analytics (lab on a chip) and especially in electronics and the consumer sector, where great interest has been shown.
This new method was born of a surprising phenomenon: irradiating glass in a particular way with an ultrafast laser has the effect of making the glass up to a...
Terahertz excitation of selected crystal vibrations leads to an effective magnetic field that drives coherent spin motion
Controlling functional properties by light is one of the grand goals in modern condensed matter physics and materials science. A new study now demonstrates how...
Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.
"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...
In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.
A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...
By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.
"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...
14.10.2016 | Event News
14.10.2016 | Event News
12.10.2016 | Event News
27.10.2016 | Materials Sciences
27.10.2016 | Physics and Astronomy
27.10.2016 | Life Sciences