July 2006
ALS Research News (A monthly summary of significant articles about ALS research)
Roberta Friedman, Ph.D., ALSA Research Department Information Coordinator
While this summary is not exhaustive, it does include some of the most recent advances. If you would like certain news items featured, please contact the Research Department at researchgrants@alsa-national.org.
Trial of Celecoxib Does not Show Benefit in ALS
Advance online publication in June in the Annals of Neurology showed that a trial of 800 mg of celecoxib in 300 ALS patients failed to slow decline of muscle strength or alter any other measures of progression of the disease. The drug was safe, as reported by Merit Cudkowicz, M.D., Daniel Drachman, M.D., and colleagues. Further trials will test a combination of this drug with creatine, as animal findings suggest the combined treatment might help in ALS.
Candidate ALS Drug Found by Proteomics, Cell Screening
Ebselen, a mitochondrial acting drug, is a candidate for treating ALS, as reported by researchers working with Pamela Shaw, M.D., of the University of Sheffield in England. The investigators found that an enzyme in the mitochondria, called peroxiredoxin 3, an anti-oxidant, is less abundant in both a cell culture model and in a mutant mouse model of the disease (the SOD1 mouse) as well as in ALS patients. Ebselen, an anti-oxidant drug that acts as a mimic of peroxiredoxin 3, is able to counter the toxicity of the mutant SOD1 protein in the cell model. These preliminary findings were published in Brain in July.
ALS Linked to Variant of Gene Involved in Pesticide Processing
In a published report by researchers at Northwestern University in Chicago led by Teepu Siddique, M.D., gene evidence suggests that differences in the ability to detoxify pesticides and nerve gases might explain why ALS occurs at higher frequency among veterans of the Gulf War, and why certain environmental exposures might increase the risk of the disease. As reported at the meeting of the American Academy of Neurology in San Diego this spring and now published on line in advance of the August issue of Neurology, variants of genes coding for the so called PON enzymes that handle pesticides and other chemicals are linked to a two-fold increased risk to develop ALS. This suggestive finding is not cause and effect but gives a place to start looking for genetic and environmental risk factors for the disease.
ALS2 Mutation Targets Upper Motor Neurons in Mice
Two publications in the June Annals of Neurology explain why it has been difficult to make a mouse that shows damage from mutation in the alsin protein implicated in a type of ALS that begins at a young age.
Investigators working with Don Cleveland, Ph.D., at the University of California, San Diego, reported online in June in the Annals of Neurology that mice missing the alsin protein show progressive degeneration of upper motor neurons traveling down the spinal cord but no damage to the lower motor neurons that go from the spinal cord to muscles. The mice moved more slowly than normal mice but did not show muscle weakness. The affected mice do not show the spasticity from upper motor neuron damage that people show. Thus alsin mutation produces a distinct disease that is not exactly the same as ALS, the researchers concluded. Instead it more closely resembles a severe form of hereditary spastic paralysis.
Reporting in the same publication, researchers working with George Haase. M.D., Ph.D., at Institut National de la Sante et de la Recherche Medicale, and AVENIR, France, show that motor neurons with depleted alsin (by a different technique than that used by the Cleveland group) die at a rate of 30 to 40 percent in culture, and surviving cells had limited ability to send out fibers. The effect of removing alsin was replicated by cells failing to make the guanine nucleotide exchange factor, Rac1, a cell protein previously implicated in the alsin mutation. Consistent with the suspected role for these proteins in the proper function of the cellular sacks called endosomes and intracellular movement of materials in general, the motor neurons with reduced alsin had shrunken endosomes and impaired intracellular traffic.
Two structural proteins interact in Hereditary Spastic Paraplegia
Two proteins that help nerve fibers stay intact and able to supply the rest of the cell with needed materials apparently can cause the disease called hereditary spastic paraplegia, which features stiffness and weakness. The proteins are spastin and atlastin, and they may have to interact properly to maintain nerve fiber health, suggested the Columbia University researchers, led by Brett Lauring, M.D., Ph.D., in their report in July in the Proceedings of the National Academy of Sciences.
…And Another Gene Implicated in this Disorder: Parallels with ALS
Stephan Züchner, M.D., at Duke University and colleagues published online in July in the American Journal of Human Genetics another gene linked to hereditary spastic paraplegia that codes for the protein called REEP1. The protein helps the mitochondria.
The conclusion to draw from these new insights into alsin function and parallels with hereditary spastic paraplegia is that motor neuron disease is linked to movement of cell supplies as well as to mitochondrial function. The ALS Association continues to fund research into these potential aspects of ALS.
Genetics of Cognitive Change That is Linked with ALS
An international collaboration has discovered a new mutation that appears to cause some cases of ALS. As reported online in Neurology June 28, the mutation to a protein called charged multivesicular body protein 2B (CHMP2B) previously associated with cognitive change was found in two unrelated patients with motor neuron disease, as published by Elizabeth Fisher, Ph.D., University College London, and colleagues. These findings add to others that implicate vesicle function in motor neuron damage.
A new gene linked to frontotemporal dementia (FTD) was reported by two independent groups, as published online in Nature July 16. This type of dementia can occur in ALS patients and may even precede the motor neuron disease in some. As reported by teams led by Michael Hutton, Ph.D., of the Mayo Clinic College of Medicine, Jacksonville, Florida, and by Christine Van Broeckhoven, Ph.D., University of Antwerp, Belgium, all of the mutations documented in various families with inherited FTD lead to premature halts in reading out the DNA, so that the cells lack sufficient progranulin, the researchers showed. Progranulin, a growth factor, is a known stimulator of VEGF, another supportive molecule linked to ALS. The findings are also relevant to findings earlier this year with the blood vessel promoting protein angiogenin, a protein similar to VEGF.
The mutated gene for progranulin is located on chromosome 17 very close to the tau mutation that produces other inherited cases of FTD. The discovery solves a decade long puzzle as to why some families with FTD lack any change in the tau gene. While these families with mutated progranulin do not show motor neuron disease, the knowledge gained by answering the genetic question of their illness will no doubt spur faster progress in finding genes that do produce ALS. Article 1; Article 2
VEGF Gene Variation Linked to Female Gender in ALS
Researchers in Germany reported in Neurology in June that the sample of about 400 patients they tested for variants of the gene for VEGF only showed a statistically significant link for females. The researchers, led by Thomas Gasser, M.D., at the Eberhard-Karls University in Tuebingen, noted that prior positive findings of a link of VEGF gene variants to increased risk of developing ALS were only found in patient samples with a relatively high proportion of females.
Chromosome 9 Location for FTD Gene Published
The team led by Teepu Siddique at Northwestern University in Chicago, published in Neurology in July the location of a region on chromosome 9 of a gene linked with FTD, as reported this spring at the meeting of the American Academy of Neurology in San Diego. The exact gene has yet to be pinpointed.
SOD1 Clues, Parallels from Alzheimer’s Disease
Mikael Oliveberg, Ph.D., and colleagues at Stockholm University in Sweden, reported in the Proceedings of the National Academy of Sciences in July that the mutant SOD1 molecule, similar to the abnormal amyloid protein in Alzheimer’s disease, has certain regions that promote clumping together when the molecules unfold under conditions within cells.
Brain Signals Can Control a Cursor or Prosthesis
Help for paralyzed people may come from the ability to convert brain signals of intentions to move into actual movement. The progress in this area by investigators working with Leigh Hochberg, M.D., Ph.D., of Massachusetts General Hospital and John Donoghue, Ph.D., of Brown University was published in Nature in July. The approach is being tested in ALS patients. The researchers demonstrated that implanted microelectrodes can read the activity of hundreds of neurons and convert these signals into useful control over computers, a light switch, a television and even a robotic hand. The investigators noted that a risk for infection is posed by the indwelling microelectrodes but also suggested in the future it could be possible to control limbs through several electrodes in different brain areas that would activate muscles through electronic interfaces.
