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.
In Nature Medicine, Janice Robertson, Ph.D., University of Toronto, and colleagues describe an antibody that specifically recognizes an improperly folded molecule linked to ALS. The antibody recognizes a disease linked form of the enzyme, copper-zinc superoxide dismutase (SOD1). Named SOD1-exposed-dimer-interface antibody (SEDI-antibody), the antibody can serve as a signal to detect when the SOD1 protein is not in its normal configuration. It did so in three different lines of mutant mice and in an ALS patient with a SOD1 mutation. The antibody also has potential as an immunization for ALS caused by mutations in SOD1. It could probe whether the enzyme is not properly folded in sporadic cases of ALS. The SEDI antibody also might prove useful for drug discovery in ALS. Investigators can contact Avi Chakrabartty or Robertson for the antibody.
TDP-43: Some Studies Show Presence in SOD1 Mutants
Robertson and colleagues also have in press in Neuroscience Letters (Volume 420, Issue 2, June 13th pp 128-132) that SOD1 mutant mice lack TDP-43 abnormalities. TDP-43 is a newly discovered link between ALS and a dementia that can occur with the motor neuron disease. It is a protein of as yet unknown function that is found in abnormal protein clumps in dying nerve cells in both diseases but perhaps not with ALS produced by SOD1 mutation. Robertson’s group did find some evidence for TDP-43 in two patients with SOD1 mutation they investigated in contrast to the mutant mice. A team working with Virginia Lee, Ph.D., Manuela Neumann, M.D., and colleagues at the University of Pennsylvania, Philadelphia, and Ludwig-Maximilians University in Munich, found that ALS patients with the SOD1 mutation do not have TDP-43 in their nervous system cells, as reported in Annals of Neurology.
A Japanese team that reported findings last month did not find TDP-43 in cases of ALS involving SOD1 mutation, but it is present in deposits in motor neurons and in the glia of sporadic ALS cases and in inherited ALS not due to SOD1 mutation (covered in April’s Journal News; note we are making a correction to our original report)
Another report in Neuroscience Letters by Japanese researchers working with Hajime Arai M.D., Ph.D., at Juntendo University in Tokyo, compared the distribution of TDP-43 to ubiquitin, another marker of abnormal protein deposits, in brains of seven patients with various types of FTD, including two with both dementia and motor neuron disease. TDP-43 generally appeared together with ubiquitin but either protein also appeared alone. In two cases of motor neuron disease examined, the proteins usually appeared together, although most glia examined in one of these cases contained only TDP-43. The pattern of TDP-43 and ubiquitin as markers of abnormal deposits of protein inside cells therefore differed among the types of FTD, a difference that may signal different types of the disease exist.
Ian Mackenzie, M.D., at Vancouver Hospital, British Columbia, working with Lee and other collaborators published in The American Journal of Pathology that TDP-43 is found in families with FTD linked to chromosome 9 but not in those with FTD linked to mutation in the protein called charged multivesicular body protein 2B.
Lee and colleagues, in Acta Neuropathologica, reported no apparent changes in FTD in proteins linked to the function of TDP-43 in human brain tissue. These are proteins that regulate how genes are read. Some other aspect of TDP-43 must be responsible for its abnormal presence in the disease, the scientists concluded.
Role for Copper Interactions in Mutant SOD1
Ashley Bush, M.D., Ph.D., at Harvard and colleagues published in Free Radical Biology & Medicine that several mutant versions of SOD1 produced in several different types of cells have increased ability to bind copper. Other scientists had reported in the Proceedings of the National Academy of Sciences (covered in April’s Journal News) that a mouse with both the mutant SOD1 protein and an excess of its normal helper, the copper chaperone for SOD1, accelerated ALS symptoms. The role of copper in the disorder has been contended; these findings bring the subject back into consideration.
Mutant SOD1 Proves Additive for Neuron Damage
Reporting in Neuroscience Letters, scientists at Boston University working with Robert J. Ferrante, Ph.D., and Jiang-Fan Chen, M.D., Ph.D., showed that providing the mutant SOD1 protein boosts damage in the brain when the mutant protein is given in cells introduced in the body. The damaging agent is able to produce a type of brain destruction similar to that in Huntington’s disease. There was no additive effect if the mutant SOD1 was introduced in cells given directly into the brain. These findings may widen the concept of the “bad” neighborhood to include the entire body as well as the brain.
Trophos Candidate ALS Therapeutic Described
Scientists at French biotech firm Trophos published details of their compound that is in early clinical trials in ALS. Reporting in the Journal of Pharmacology and Experimental Therapeutics, Christopher Henderson, Ph.D., who recently received the Essey award for ALS research, together with Rebecca Pruss, Ph.D., and colleagues showed that compound cholest-4-en-3-one, oxime (TRO19622) works at the mitochondria, the cellular power supplies, and extends survival in the SOD1 mutant mouse model of ALS. More info
Stem Cells Make Connections as Motor Neurons
Lorenz Studer, M.D., Viviane Taber, M.D., and colleagues at the Sloan Kettering Institute in New York City, report a new protocol to generate motor neurons from human stem cells. Reporting in Stem Cells, the researchers found long nerve fibers from the generated motor neurons extended long distances when grafted into chick embryos. They also achieved successful implants of these cells into rat spinal cord: the nerve endings showed the presence of expected messenger molecules.
Less Success with Marrow, Umbilical Derived Cells
Limited success with stem cells was reported by Albert Ludolph, M.D., at the University of Ulm, Germany, and colleagues who published in the Journal of Neural Transmission that cells derived from human bone marrow called mesodermal stromal cells, as well as umbilical cord blood cells, had little ability to aid in the mouse model of ALS. They directly injected the cells into the fluid that bathes the brain and spinal cord. Ten days after the transplant, only a few cells could be seen around the spinal cord. Survival times of the mice did not change with the treatment. Strategies will have to be explored to improve the delivery of transplanted cells into the regions of interest for the treatment of ALS, the researchers concluded.
Wlds Mouse Reveals Nerve Protective Response
Researchers at the University of Edinburgh working with Thomas Gillingwater, Ph.D., reported in Molecular & Cellular Proteomics on changes in proteins in mice with a mutation that extends the life of nerve fibers after they are severed from their cell bodies. The mice with the so called Wlds mutation had changes in the amount of 16 proteins, eight of which are known to regulate the mitochondria. Other proteins governing these cellular power suppliers are also changed by the mutation at the synapses, and several are implicated in neurodegeneration.
MUNE a Useful Progression Biomarker for ALS
A team working with Hiroshi Mitsumoto, M.D., of Columbia University published in Neurology a comparison of several possible means of following ALS progression, including brain imaging and signal conduction along nerves, as well as motor unit number estimation (MUNE), an electrical measure of the integrity of the nerve to muscle connection. None of the measures other than MUNE could tell ALS patients from normal people for diagnosis. MUNE also was the most reliable marker of progression, although the other methods show promise for understanding the biology of the disease and could become more useful in the future, the researchers concluded.
Vincent Meininger, M.D., Ph.D., at the Pitié-Salpêtrière Hospital in Paris, and collaborators published findings presented at the meeting of the American Academy of Neurology in Boston that Nogo A content of muscle might be able to serve as a diagnostic marker of ALS. Thirty-three patients with only lower motor neuron symptoms who had muscle biopsy during their diagnostic workup were observed for a year. Nogo-A correctly identified patients who further progressed to ALS with 91% accuracy, 94% sensitivity, and 88% specificity. Nogo-A was detected in 17 patients but absent in 16 patients. The findings suggest that Nogo-A may be detected as early as three months after the onset of symptoms in disease that turns out to be ALS.
John Ravits, M.D., and colleagues at Virginia Mason Medical Center in Seattle, Wash., published two papers in Neurology that provide a detailed analysis of the loss of motor neurons in the brain and spinal cord. The investigators concluded that neurons in the brain and the spinal cord die independently. The dying of neurons begins in a distinct location and spreads in the spinal cord from that focus. This is more easily detected in the spinal cord than in the brain due to the way the neurons are organized in the spinal cord. For most patients, the loss of motor neurons was greatest at the region controlling the body part of onset and was less marked at the more distant regions of the cord controlling body parts affected later in the disease. More info
