June 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.
Stem Cell Update
This month saw many key publications in the stem cell field that encourage those seeking to help treat motor neuron disorders.
The group led by Douglas Kerr, M.D., Ph.D., at Johns Hopkins University, showed that stem cells prompted to form motor neurons and then placed in rat spinal cord can partially restore function. As published in the Annals of Neurology in July, the implanted motor neurons could form working connections with target muscles. The rats had been given a viral infection that specifically killed their own motor neurons and as a result were paralyzed. The important points are that connections to muscle could be made, and this required a cocktail of treatments to overcome the inhibitory action of proteins made by myelin in order to reestablish function. This cocktail approach had been discussed at the workshop on stem cells at Banbury Center, Cold Spring Harbor, sponsored by The ALS Association. For more information, click here and here.
Other research at Hopkins reported by Vassilis Koliatsos, M.D., and collaborators shows that stem cell transplants into SOD1 mutant mice allow longer survival if given with immune suppression. These researchers also showed connections established by implanted cells and delayed onset of disease in mice with surviving grafts, according to the report online in April in Stem Cells.
The developmental signal molecule called Notch can boost the brain’s own stem cells to avoid stroke damage in mice, as reported in Nature. Researchers working with Ronald D. McKay, Ph.D., at the National Institute of Neurological Disorders and Stroke in Bethesda, Md., reported in Nature that providing certain signal molecules can boost the brain’s own stores of stem cells to avert damage by a stroke in mice. The model of stroke used was to tie off a major artery to the brain. This gives a hint of what might be accomplished if therapy could be devised to target the intrinsic stores of stem cells in the body.
Even Skin Might Serve as Stem Cell Source
As reported in the Journal of Neuroscience in June, Freda Miller, Ph.D., and collaborators at the Hospital for Sick Children Research Institute in Toronto, Canada, showed that both rats and humans can produce stem cells from their skin. They demonstrated that stem cells derived from rat skin could produce myelin cells that would wrap around nerves in mice that lack their own myelin insulation.
Stephen Davies, Ph.D., and colleagues at Baylor in Houston, showed that stem cells that form the supporting cells of the nervous system called astrocytes can repair rat spinal injury, as reported online in the Journal of Biology in April. The implanted astrocytes suppressed initial scarring and rescued neurons whose fibers were cut. Placing these astrocytes into the site of the cut in the spinal cord promoted growth of more than 60% of nerve fibers into the centers of the injury, with 66% of these nerve axons extending beyond the injury sites. Transplanted rats showed better ability to walk.
How will stem cell derived cells know where to go? The growth factor called FGF may be a key signal that allows motor neurons to find the right muscle to connect to and to contract, according to a report in June in Neuron by Salk Institute researchers led by Samuel Pfaff, Ph.D., in La Jolla, California.
Many different routes are available for researchers to explore toward the goal of an effective stem cell therapy for ALS and other disorders. The ALS Association will seek to fund any avenue that could show promise. Of note is that patients treated in China for spinal injury with a preparation of fetal cells described as olfactory ensheathing cells have not shown any evidence that the treatment worked. Instead many of the seven patients with spinal cord injury checked by other physicians had potentially harmful side effects in the days following the expensive procedure, as mentioned briefly in last month’s monthly journal news. This issue was the focus of an article published by the Boston Globe which quoted Lucie Bruijn, Ph.D., science director and vice president of The ALS Association.
Why Minocycline Might Help in ALS
Researchers might have a better handle on why minocycline and related drugs work to protect the nervous system. Minocycline is in clinical testing as a candidate therapy for ALS. Led by Raymond A. Swanson, M.D., a San Francisco VA Medical center team identified the target of minocycline’s protective action, a molecule called poly(ADP-ribose) polymerase-1, as reported online in June in the Proceedings of the National Academy of Sciences. This protein is known to trigger inflammation and cell death, processes known to be affected by minocycline. With this mechanism in hand, researchers can look for even more effective drugs to help ailing nerve cells.
In the June Journal of Neurochemistry, a group at the VA Medical Center in Kansas City, Mo. reported that minocycline is able to help in rodent models of spinal cord injury and give evidence that its action is due to decreased tumor necrosis factor-alpha, as well as caspase-3, players in inflammation and cell death respectively. The report is from the team including Barry Festoff, M.D., and Bruce Citron, Ph.D.
Non Invasive Ventilation Aids Patients, Does Not Add Caregiver Burden
Nigel Leigh, M.D., at King’s College Hospital, U.K., and colleagues found that ALS patients with weakness of the respiratory muscles lived longer when given noninvasive ventilation, and their quality of life improved, although cognitive function did not. Caregivers did not have increased burden, as compared with caregivers of patients without respiratory weakness or patients not using or unable to tolerate noninvasive respiratory support. This is the largest prospective look to date to demonstrate the advantages of ventilatory support for both survival and quality of life. The investigators deemed it unethical to randomize patients to receive the treatment due to already existing evidence that this treatment is beneficial. The study was published in April in Neurology.
Patients using noninvasive respiratory support will likely need to adjust settings upward as their disease progresses, according to a longitudinal study by Eva Feldman, M.D., Ph.D., and collaborators at the University of Michigan, Ann Arbor, reported in April in the Journal of the Neurological Sciences. Those patients who tolerate relatively low settings tend to survive longer.
Possible Biomarker in Electrical Response of Nerves
Australian researchers at the Royal Brisbane and Women's Hospital working with Jasper Daube, M.D., demonstrated that the response to electrical stimulation to define the so- called compound muscle action potential can distinguish ALS patients. This measure reported in April in Muscle & Nerve might serve as a way to follow progression and response to treatment.
Tau Protein and Cognitive Change in ALS
Michael Strong, M.D., and colleagues at Robart's Research Institute in London, Canada, published in Neurology in June that the protein called tau is tagged with many phosphate molecules in patients who died with ALS and cognitive impairment, as is also the case for patients who died with Alzheimer’s disease. This is an example of how some of the key proteins in Alzheimer’s Disease are now being implicated in ALS.
…and a Drug May Help with Tau
German researchers working with Hanno M. Roder, Ph.D., at Sirenade Pharmaceuticals, Martinsried, and collaborators at the Mayo Clinic in Jacksonville, Florida reported in the Proceedings of the National Academy of Sciences in June that a compound related to one called K252a, but with the added ability to enter the brain, can help in mice with motor defects due to too much phosphate tagging of the tau protein. Motor behavior and accumulation of tau protein both responded to the treatment in the mice.
Alsin Advances Give Insight into ALS
A new mutation that produces an accelerated motor neuron disease beginning in childhood is described by an international team including Don Cleveland, Ph.D., at the Ludwig Institute, University of California, San Diego, and Odile Boespflug-Tanguy, M.D., Ph.D., at Institut National de la Sante et de la Recherche Medicale in Clermont-Ferrand, publishing in May in the Annals of Neurology. The mutation in the ALS2 gene produces infantile ascending hereditary spastic paralysis, a disease of the upper motor neurons. The gene change is predicted to affect the functioning of the so-called guanine exchange factor, a protein which helps package and handle cell materials.
The alsin mutation apparently leads to increased cell death, Italian researchers reported in Brain in May. Maria Bassi, Ph.D., and colleagues at the IRCCS E. Medea, Laboratory of Molecular Biology, Bosisio Parini Lecco, Italy, showed that a juvenile onset form of primary lateral sclerosis is due to mutation in the ALS2 gene as well. The group analyzed a patient and family members to find the gene change. The investigators then showed, in laboratory grown cells, that the ratio of cell death proteins Bcl-xL and Bax is safeguarded by normal alsin and is the site of the toxicity of the mutant form.
Alsin Supplies Trophic Factor Receptors
The alsin mutation in mice hinders transport of vital nurturing materials and produces mice that are slightly less active than normal, according to findings reported in the Proceedings of the National Academy of Sciences in June. Receptors for the so-called neurotrophic factors move more slowly toward the nerve endings, according to findings in alsin mutant mice by researchers working with Michael Hayden, Ph.D., at the University of British Columbia in Vancouver.
Trophic Factor Receptors Lost in SOD1 Mutant Mice
The receptors for the trophic factors are not always abundant on adult motor neurons as compared to developing animals and some are even less abundant in SOD1 mutant mice, according a report by Eric Huang, Ph.D., at the University of California, San Francisco, to be published in the Journal of Neurobiology in July. This study, funded by The ALS Association, shows loss of much of the receptors called GFRalpha1 and -2, yet the molecule that carries the signal farther along is not changed—the phosphorylation of c-ret is the same in adults as in young mice and in SOD1 mice, and abundance of TrkB is not changed by the SOD1 mutation.
Cell death switch implicated in ALS
Maria Teresa Carri, Ph.D. at the University of Rome "Tor Vergata," and colleagues reported in Cell Death and Differentiation in May that the cell death molecule called Bcl2a1 in mice is present in neurons and in high levels in SOD1 mutant mice, even before symptoms appear. The increase is only in the spinal cord and not in brain or muscle in these mice. The molecule apparently is expressed specifically by the motor neurons. The decline in the molecule that occurs at end stage could reflect the loss of the motor neurons. This newly identified signal of the disease in mice could guide researchers toward a therapeutic target.
Another Clue that ALS Affects Mitochondria
The action of rotenone, a mitochondrial poison, is accelerated by SOD1 mutation in cells growing in the lab. Lavinia Cantoni, Ph.D., and colleagues at the Mario Negri Institute in Milan, Italy, reported in April in Brain Research Bulletin that mitochondria from cells expressing mutant SOD1 are more vulnerable to cell death after rotenone, a pesticide, disrupts the electron transport chain in these power suppliers of the cell.
Dutch researchers describe a signal molecule called semaphorin 3A that is on the nerve endings in fast-fatiguing muscle fibers. These are the nerve endings that fail to regrow well after various injuries. Joost Verhaagen, Ph.D., and colleagues at the Netherlands Institute for Brain Research in Amsterdam, reported in May in Molecular and Cellular Neurosciences that the protein is present in a mouse model for ALS at the nerve endings on fast-fatiguing muscle fibers. They propose that the protein suppresses repair at this type of nerve-muscle junction and might contribute to its early and selective loss in ALS.
As published in June by Andrew Lieberman, M.D., Ph.D., and colleagues at the University of Michigan in Ann Arbor, in Human Molecular Genetics, a role of a guiding molecule called hsp90 is now more clearly defined in Kennedy disease, a motor neuron disorder that has similarities to, and could give clues for, ALS. Apparently hsp90 in Kennedy disease may actually promote abnormal protein aggregation, as stopping the action of hsp90 lessens the aggregation.
Hampering the transport of proteins within cells, as well as the aggregation of proteins, may underlie several adult-onset neurodegenerative diseases, such as Huntington's, ALS and Kennedy disease. As published online June 4 in Nature Neuroscience, researchers working with Scott Brady, Ph.D., at the University of Illinois, Chicago, showed that Kennedy disease interferes with so-called "fast axonal transport" that moves proteins inside cells from where they are made to where they are needed. The mutated protein in the disease hindered fast axon transport by activating an enzyme called JNK. The link to the JNK enzyme suggests a new target for therapy design and explains why only nerve cells die--and why the terminals die before the cell body. Researchers on the project include Gerardo Morfini, Ph.D., who is investigating the role of axonal transport in ALS with funding by The ALS Association.
