December 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.
Chromosome 9 Location Narrowed for Gene for ALS, FTD
The location on chromosome 9 for a gene that is changed in families with cases of ALS and FTD has been narrowed. The findings to be published in Archives of Neurology will help pinpoint the exact gene change, as reported by Paul Valdmanis, BSc., with a team led by Guy Rouleau, M.D., Ph.D., at the CHUM Research Institute, Notre Dame Hospital, in Montreal. The new families with inherited ALS and FTD add to the existing information from other families to help investigators isolate the responsible mutations. Please see prior reports covered in the monthly journal news in February 2006.
Neurons Unique to Apes and Humans Linked to FTD
Large neurons that appear only in highly evolved brain regions linked to cognitive and social skills in humans and only as they mature are apparently affected by FTD, the cognitive change that can occur in some cases of ALS. The discovery made in brain material donated after death by investigators at the University of California, San Francisco, and colleagues provides a target cell for this disorder and potentially a target for designing therapeutics. The findings were reported at a conference on FTD in San Francisco this fall along with the discovery of a protein common to FTD and ALS. The team led by Bruce Miller, M.D., and William Seeley, M.D., at UCSF published their findings on the so-called von Economo neurons in the online Annals of Neurology in December.
Rapid Cognitive Test for ALS Patients Proposed
A shortened cognitive testing panel is proposed by Penn State researchers in Hershey led by Zachary Simmons, M.D., to show which ALS patients might be at risk for cognitive change.
Trial Designs Discussed for ALS
Strategies to maximize ALS clinical trials by finding the highest dose of a candidate that can be given with minimal side effects and by comparing two candidates in a so-called selection design are presented in November in Neurology. The approach is illustrated by an ongoing trial funded by The ALS Association’s TREAT ALS initiative, as discussed by Paul Gordon, M.D., and Bruce Levin, Ph.D., at Columbia University in New York.
The use of database information to aid either pilot or futility trials in ALS is discussed in the same issue by the team led by Stanley Appel, M.D., at Methodist Neurological Institute in Houston, Texas. This approach can obviate the need for a placebo in smaller Phase II trials, but a placebo control will still be required in pivotal Phase III testing of any candidate treatment to definitively show the drug works.
Angiogenin Levels Increased in Some ALS Patients
Blood serum levels of angiogenin but not VEGF appeared higher in a sample of ALS patients at diagnosis compared to matched controls, as reported by Irish investigators in Neurology in November. The increase was statistically significant. Further investigation will be needed to see if the difference appears in a larger sampling of patients and if it is clinically relevant.
Free Radical Scavenger in Small Trial in ALS
Japanese researchers published findings in 20 people with ALS who tolerated treatment with a compound called edaravone that mops up free radicals. Two weeks of intravenous drip treatment, followed by two weeks off the treatment, was repeated six times. The ALS Functional Rating Scale indicated the patients might have progressed more slowly than expected given their own prior rates of progression. A larger trial might be able to show if the treatment is effective.
Senataxin Gene in Yeast Impairs Proper Gene Messages if Mutated
The yeast version of a gene mutated in rare forms of inherited ALS will impair translation of DNA if mutated, according to research published by University of Wisconsin researchers led by David Brow, in December in Molecular Cell. Mutated Sen1 will not stop properly at the end of a coding sequence in DNA, disrupting the production of protein. Mutations in the human version, senataxin, can produce ataxias as well as the rare form of ALS.
Findings Published to Suggest Muscle Does Not Initiate ALS Disease
Brian Kaspar, Ph.D., of the Columbus Children’s Research Institute and colleagues published in December in the Proceedings of the National Academy of Sciences data presented at the meeting of the Society for Neuroscience in Atlanta. Boosting muscle mass and strength in the SOD1 mutant mouse model of the disease by using a muscle growth helper called follistatin did not alter disease onset or progression, the scientists reported.
Blood Booster Saves Motor Neurons, Schwann Cells a Reason?
Italian researchers published that molecules based on the red blood cell boosting molecule, erythropoietin (EPO), can reduce loss of motor neurons in a mouse with the so-called wobbler mutation, a model used in ALS research before the advent of the mutant SOD1 transgenic mouse. A preliminary report of a small patient trial in Korea was made at the Yokohama meeting of MND/ALS with erythropoietin showing safety and a suggestion of efficacy. Blinded, placebo-controlled testing will have to confirm. EPO appears to bind to a receptor on the Schwann cells that insulate nerve fibers, acting there to decrease the inflammatory mediator, TNF alpha.
The SOD1 Mutant Transgenic Mouse
As discussed in a session at the Yokohama meeting of the Motor Neurone Disease Association this month, the SOD1 mutant mouse that expresses the human gene mutated in some inherited ALS is perhaps limited as a model due to variability in its genetic background, and perhaps more importantly, due to animal testing that should be as rigorous as clinical trials in people. Blinding as to which animals are on active treatment is required to avoid bias. Following are some relevant, recently published studies on the mouse.
Detailed Description of Molecular Changes in SOD1 Mutant Mice
The molecular changes evident in the mouse model are described minutely in a report by Johns Hopkins researchers, including Lee Martin, Ph.D., in the Journal of Comparative Neurology. The process appears not to involve programmed cell death, but injury to mitochondria is evident as well as inflammatory changes and loss of spinal interneurons.
SOD1 Mice Show Respiratory Change
Jeff Rothstein’s team at Johns Hopkins in Baltimore showed that the mice have changes in respiration quite similar to ALS disease progression.
Mice Lacking Any SOD1 Not Entirely Normal
The SOD1 mutation in ALS is though to be due to a gain of a toxic property by the mutant protein, especially since mice lacking the normal protein appear to live normally. However, this is called into question by a report by John Faulkner, Ph.D., and colleagues at the University of Michigan, Ann Arbor. As reported online in November in Cell and Tissue Research, mice lacking the normal SOD1 protein are healthy but are slightly smaller, with smaller muscle and heart mass and show subtle changes in muscle and nerve distribution to muscle.
Glutamate Receptors Differ on Motor Neurons Spared in ALS
Researchers in New Zealand reported in Neuroscience that in human brain the motor neurons most vulnerable in ALS—those in the face and the tongue and palate—have higher levels of a type of glutamate receptor, the metabotrophic receptors 1 and 5, than those motor neurons that are affected last in the disease—those that control eye movement. The study was led by Louise Nicholson, Ph.D., of the University of Auckland.
Spastin Mutation Impairs Microtubule Dynamics
Reporting in December in Human Molecular Genetics, researchers led by Judith Melki, M.D., Ph.D., at INSERM and the University of Evry, France, show that a mutation in the protein, spastin, produces damage to motor neurons near the termination of the brain’s nerve endings on the target nerves in spinal cord. This process might be similar to what happens in ALS. Spastic paraplegia is the destruction of the nerve tracts from brain to spinal cord, and this occurs along with the death of motor neurons from the cord to muscles, as well in ALS. Apparently the interruption of axonal transport occurs near the growth cone in the axon with spastin mutation. Distal damage near the axon terminals may also be the case with SOD1 mutation in some inherited ALS (see here). Spastin mutations are just one cause of hereditary spastic paraplegias, similar to the situation in ALS where many different proteins might be mutated in different instances of ALS. Comparative study of both diseases and all of the responsible mutations might provide the common key to how motor neurons die and how to help stop the processes.
Neurofilaments and Too Much Glutamate May Add Up in ALS
Researchers collaborating with Michael Strong, M.D., at the Robarts Research Institute in London, Ontario, Canada reported findings that suggest neurofilament aggregation can influence the toxic response to too much of the glutamate messages, both implicated in ALS. Publishing in January in Free Radical Biology & Medicine, the researchers used mice with a mutation that makes the support structures within nerve fibers, called neurofilaments, clump abnormally. Neurons taken from these mice show increased sensitivity to the excitotoxic agent abbreviated NMDA, and the inflammatory mediator, nitric oxide, may reverse this. The model supports the thinking that a complex interplay of protein misfolding, excitation, and inflammation takes place in the disease process of ALS.
Environmental Factors in ALS: An Update
Studies of exposures during a person’s life that might risk ALS, as in all works of epidemiology research, are unable to determine cause and effect. Only association can be documented at best. Study design and statistical analyses are crucial. Following are additions to the literature this month on what risk factors in the environment might skew toward ALS. This is timely as discussion at Yokohama included whether genetic differences in indigenous peoples of the Pacific Rim might explain the ALS-like disorders on Guam and the Kii peninsula in Japan linked by some to diet.
Stearyl Glucosides in Cycads, Bacteria, are Toxic
Christopher A. Shaw, Ph.D., at the University of British Columbia, and colleagues published evidence that compounds in cycad and also in bacteria are toxic in nerve cells growing in the lab and in mice. The report was published online in December in the Journal of Neuroscience Research.
Study Fails to Support Risk of ALS in Tobacco Use
Swedish investigators reported online in Neuroepidemiology that use of snuff or smoking tobacco does not associate with increased risk of ALS among men. The study at the Karolinska Institute in Stockholm was led by W. Ye.
Electric Injury Not Associated with ALS
Investigators working with P. Nigel Leigh, M.D., could not confirm prior reported association of electrical shock injury with ALS.
Pyrethrin Misuse Produces Reversible ALS
Japanese clinicians reported a woman who used the pesticide pyrethrin in an unventilated area for many years developed a disorder very similar to ALS that partially resolved once she stopped contact with the product. As reported in November in Neurology, the possibility exists that some people metabolize this pesticide slowly and might be more sensitive to it.
Metal Detoxifying Unaltered in ALS
Roger Pamphlett at the University of Sydney, Australia, and colleagues showed that the handling of heavy metals is not changed in ALS. A family of detoxifying enzymes do not show any differences in how their genes might be activated or not transcribed in brain samples from patients who died of ALS.
