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.
Gene Changes In Mice Modeling ALS: Some Surprises
Motor neurons in mutant SOD1 mice are expressing elements of the immune system in findings that tie in with recent evidence for secreted toxic SOD1 as a potential event in ALS, according to research findings of Christian Lobsiger, Ph.D., working with Don Cleveland, Ph.D., at the Ludwig Institute at the University of California, San Diego, and colleagues, published online in the Proceedings of the National Academy of Sciences. In minute amounts of tissue captured by laser, the researchers highlighted changes in gene activities for three pathways in the mutant mice: the serine biosynthetic pathway that affects potentially toxic nerve messages, complement genes that mobilize the immune system and genes for attempted repair of nerve fibers. Complement activation, recruiting the immune system to dispose of damaged cells, is evident in the gene activities of neurons from the mutant SOD1 mice and is also apparent in Alzheimer’s and other neurodegenerative diseases, the investigators noted. This information gives vital clues to therapeutic avenues.
Erythropoietin Possibly a Marker of ALS Progression
German researchers working with Albert Ludolph, M.D., at the University of Ulm, Germany, published findings in Neuroscience Letters that suggest a role for the hormone, erythropoietin (EPO, a stimulant of red blood cell formation), as a marker in ALS progression. Patients who had slower progression could be distinguished from rapidly progressing patients on their decreased content of EPO in cerebrospinal fluid that bathes the brain and spinal cord. No changes were evident for EPO levels in blood. Findings are also being reported at the meeting of the American Academy of Neurology at the beginning of May in Boston.
New Mouse Shows Paradoxically Accelerated ALS Symptoms
Reporting in the Proceedings of the National Academy of Sciences, Jeffrey Elliott, M.D., at the University of Texas Southwestern Medical Center in Dallas, and Giovanni Manfredi, M.D., Ph.D., at Cornell University, and colleagues have produced a mouse with accelerated ALS symptoms paradoxically by combining the mutant SOD1 protein and an excess of its normal helper. CCS is the copper chaperone for SOD1, providing the enzyme with its copper molecule, which helps the protein to properly assemble and go to the correct cellular locations. SOD1 mutant mice typically develop symptoms at 180 days and die at around 240 days, but the dual-gene mice showed symptoms by day 11 and most survived little more than a month. Mutant SOD1 was significantly higher inside mitochondria in the dual gene mice than in normal or ALS model mice, highlighting the role of this cell organelle.
ALS-Linked Proteins Interact in Nerve Fibers
Haining Zhu, Ph.D., and colleagues at the University of Kentucky reported in the Journal of Biological Chemistry that the mutant SOD1 protein responsible for some inherited forms of ALS can interact with the dynein complex in cells as well as in transgenic animals. Mutant SOD1 protein and parts of the dynein protein complex appear together in protein deposits in spinal cords and sciatic nerves in mutant SOD1 transgenic mice, they report. This association between the proteins might explain slower axonal transport in mutant SOD1 transgenic mice.
Heat Shock Protein May Have ALS Role
Japanese investigators at Kyoto University working with Shun Shimohama, M.D., Ph.D., at the University of Kyoto reported in the Journal of Neurochemistry that a heat shock protein, Hsp 105, was lower in concentration during progression of symptoms in the SOD1 mouse model of ALS, while other heat shock proteins were increased. Hsp 105 suppressed formation of abnormal clumps of the mutant SOD1 protein in lab grown cells, they also reported. The role of these cellular protectors is widely investigated, and no conclusive evidence yet pins the disease on any one of these molecules.
Serotonin Messages Implicated in Slowly Progressing ALS
The gene change in SOD1 that produces a slowly progressing form of ALS, the D90A mutation, coexisted with a relatively preserved function of the nerve messenger serotonin in patients examined by PET scanning, according to investigators P. Nigel Leigh, Ph.D., Martin Turner, Ph.D., and colleagues in the U.K. and at Umea University, Sweden. Serotonin is a nerve cell messenger that may provide the ability to modulate the progression of the disease the investigators speculated in their report in Neurology.
SOD1 Protein Change Protects Lab Cells from Toxicity
Jeffrey Agar, Ph.D., at Brandeis reported in the Journal of Biological Chemistry that a change to the mutant protein, SOD1, responsible for some inherited cases of ALS, can decrease the tendency of the protein to abnormally cluster together. The oxidation of the amino acid at a certain position (tryptophan at position 32) in the protein appears to promote aggregation, both for normal and mutant SOD1. Less aggregation occurred in mouse motor neurons grown in the lab if a different amino acid is present at this position that is less susceptible to damage from reactive oxygen.
Targeted Gene Investigation Fails to Find ALS Factors
An international team led by Elizabeth Fisher, M.D., at the Institute of Neurology in London, reported in Brain results of a search for gene variation in British people with ALS. They searched for variants in genes known to be involved in many suspect areas of the disease process, such as transport of cellular supplies along the nerve fiber and metabolism of toxins but could not find any genes in these known, suspect pathways linked to the disorder.
Non-Hispanic Caucasians May Show Higher Incidence of ALS
Bryan Traynor, M.D., Orla Hardiman, M.D., and colleagues at Beaumont Hospital, Dublin, Ireland, reported in Neurology that systematic review of the literature suggests a slightly lower incidence of ALS in people of Hispanic, Asian and African origins.
Protective Gene Change Linked to Changes in Other Genes
The Wlds mutation protects mice against several types of motor neuron disorders. Swiss investigators found changes in other genes that might explain the protection, as published in the Journal of Neurochemistry. Genes related to the function of the scaffold in nerve fibers and in particular to transport of cell materials along these axons were sought and identified by researchers, led by Ann Kato, Ph.D., at the University of Geneva. They crossed Wlds mutant mice with the pmn mouse, a model of a motor neuron disease (pmn for progressive motor neuronopathy) and looked for changes in genes in tissue from laser capture dissection and gene finding analysis. The results confirm the importance of axon function in this model of motor neuron disease, a model also being used to study ALS.
Glatiramer Not Effective in Mouse Model of ALS
Christine Haenggeli, M.D., and colleagues at Johns Hopkins could not find any beneficial effect of this proposed ALS treatment in mice modeling the disease. As published in Neurobiology of Disease, two different mutant mice that recreate many aspects of ALS did not improve with the vaccine, a high molecular weight version, TV-5010. Glatiramer is effective in multiple sclerosis. If anything, it accelerates ALS in the mice.
Survival Pathway in Neurons: No Changes in SOD1 Mice
The Akt pathway suspect in ALS does not show any changes in mice with SOD1 mutation, reported Italian investigators working with Ettore Beghi, M.D., of the Mario Negri Institute in Milan. As presented in Molecular and Cellular Neuroscience, the tissue from the specific part of the spinal cord affected by ALS, the ventral horn, showed no changes in levels of various proteins in this pathway as disease progressed in the mice.
Fat Metabolism Changed in ALS Mouse Model
Jean Philippe Loeffler, Ph.D., at Louis Pasteur University, Strasbourg, France and colleagues reported in the Journal of Lipid Research that energy metabolism in mice with mutant SOD1 reflects an increase in the use of lipids. ALS patients also show an accelerated metabolic state that can be addressed by a high fat diet. In the mice, liver metabolism of fats was normal, but absorption of lipids from the stomach and intestines was increased as was clearance of lipids from the bloodstream. This metabolic shift probably accounts for the protective effect of dietary lipids in this model, the investigators concluded.
Cognitive Aspects of ALS Demonstrate a Continuum
In a series of 30 ALS patients presenting at a multidisciplinary clinic, cognitive changes appeared in a continuum from normal to mild to impaired, according to a report by Catherine Lomen-Hoerth, M.D., Ph.D., and colleagues at the University of California, San Francisco, in Archives of Neurology. Half of the patients were cognitively normal, and the rest had evidence of frontotemporal involvement by imaging and cognitive testing. One had evidence of Alzheimer’s disease. Patients ranged in age from 27 to 80 years. The presence of cognitive impairment in ALS will be discussed in detail in June at the second international conference convening in Ontario, Canada, on this topic (click here & here).
TDP-43 Still a Mystery Protein
Virginia Lee, Ph.D., Manuela Neumann, M.D., and colleagues at the University of Pennsylvania and Ludwig-Maximilians University in Munich, published in Acta Neuropathologica on the possible role of the newly identified protein in frontotemporal dementia and ALS, called TDP-43. They did not find any evidence that this so far mysterious protein has a role in transcribing genes properly, as was initially suggested.
Earlier in this journal (Acta Neuropathol, 2007 Feb 27) Hitoshi Takahashi, M.D., and colleagues at the University of Niigata, Japan, reported on brains and spinal cords from four cases of inherited ALS, two with SOD1 mutation as well as three cases of sporadic ALS and three control subjects. Deposits were clearly positive for TDP-43, but the so-called Bunina body clumps were negative for this protein. Patients with SOD1 mutation did not have TDP-43 in the aggregates. Yet the glial cells had deposits containing TDP-43 in all cases of ALS.
ALS Patients Show Altered Emotional Reactions
Niels Birbaumer, Ph.D., and colleagues at the University of Ulm, Germany, reported in the Journal of Neurology that ALS patients show reduced arousal to facial expressions showing emotion in the anterior insula, a brain area linked to processing of aversive stimuli. ALS patients appear to have an altered sensitivity to socially relevant emotional cues, a characteristic present in frontotemporal dementia.
ALS and FTD: Patient with ALS Family History Shows Progranulin Mutation
Reporting in Neurology, an international team led by Jordan Grafman, Ph.D., at the National Institutes of Health and Bernardino Ghetti M.D., at the University of Indiana, Indianapolis, found that a patient with symptoms of frontotemporal dementia (FTD) had a progranulin gene change and also a family history of ALS. This finding suggests that ALS might be produced by a change in the function of the progranulin protein, as is the case for some instances of FTD.
Stem Cell Implant Aids SOD1 Mutant Mice
Italian investigators working with Giacomo Comi, M.D., University of Milan, reported in Brain that placing stem cells primed to become motor neurons extended survival by a couple of weeks in mice that have mutation to the SOD1 protein, a gene change responsible for some inherited cases of ALS.
