ALS Research Journal News - February 2007

SOD1 Gene Changes and ALS

French investigators demonstrated an early change in the electrical responses of motor neurons in tissue from mice with the mutation in copper-zinc superoxide dismutase (SOD1), the gene for the protein changed in some inherited forms of ALS. Jacques Durand and colleagues at Aix-Marseille University published in the European Journal of Neuroscience that the motor neurons in spinal cord tissue preparations from the transgenic animals already had differences in the second week after birth when the young mice start to bear weight and walk instead of crawl. The electrical changes suggest some change in the circuitry of the motor neurons is already taking place as the nervous system is finalizing its organization, long before actual symptoms appear, the researchers wrote.
http://www.ncbi.nlm.nih.gov/pubmed/17284186

Cocktail Corrects Mutant Tissue Toxicity in Lab Dishes

Douglas Kerr, M.D., Ph.D., and colleagues at Johns Hopkins published in the Annals of Neurology that reversing the toxic action of spinal cord tissue from mice with a SOD1 mutation requires a combination of molecules, and that such a combination might be worth trying in the clinic. The combination consisted of a scavenger of reactive oxygen, vascular endothelial growth factor (VEGF), and neutralizing inflammatory mediators called interleukins. This treatment allowed co-cultured motor neurons to survive and grow. Combination approaches to ALS treatment are the subject of existing and future trials through the TREAT ALS initiative funded by The ALS Association.
http://www.ncbi.nlm.nih.gov/pubmed/17192933

Vitamin Anti Oxidants Do Not Aid ALS

The Cochrane Reviews covered antioxidant therapy in ALS, discussing the lack of conclusive evidence that the treatment strategy works. So far studies on anti oxidants, which include vitamins C and E, have not been sufficiently well designed to determine efficacy. But low cost and high safety make it likely that doctors will continue to use these treatments in ALS patients.
http://www.ncbi.nlm.nih.gov/pubmed/17253482

Most Promising ALS Candidates by Mouse Meta Analysis

Michael Benatar, D.Phil., MBChB, at Emory University published in Neurobiology of Disease a meta analysis of treatment trials in the SOD1 mouse, showing that anti- inflammatory and antioxidants might be the most promising to try in clinical trials. These include Cox-2 inhibitors, minocycline, and creatine, as well as the anti oxidant AEOL-10150. A combination trial funded by The ALS Association’s TREAT ALS initiative is testing three of the four in combinations. Benatar and colleagues are working toward a preventive trial in people with the SOD1 mutation that causes some inherited forms of ALS, and his analysis is a step toward selecting an appropriate test therapy. He points out researchers have not been reporting negative results, which tempers conclusions about which drugs to enter into clinical trials. He also emphasizes that animal studies require proper blinding and random assignment to treatment or placebo, and that statistical significance is only meaningful in the context of clinical significance. Benatar will present the findings at the May meeting of the American Academy of Neurology in Boston.
http://www.ncbi.nlm.nih.gov/pubmed/17300945

Toxic Molecule Found in ALS Patients and SOD1 Mice

Japanese investigators found a toxic molecule in the spinal cord of both ALS patients and mice with the mutation linked to some inherited forms of the disease. Crotonaldehyde is a product of oxidative fat metabolism and is found bound to protein in the mice and in people who died of ALS and had the SOD1 mutation, as reported by the researchers led by Makio Kobayashi, M.D., at Tokyo Women’s Medical University which was published in Neuropathology. The toxic product is found in both motor neurons and in their surrounding glial cells.
http://www.ncbi.nlm.nih.gov/pubmed/17319283

Protein in ALS Aggregates Also Appears in Mouse Model

Researchers at the University of Kentucky, Lexington, documented in the SOD1 mouse model the same protein in aggregates discovered in ALS patients and reported last year by Japanese investigators. The protein, called p62, appears to reflect the ubiquitin tagging of proteins that clump abnormally within nerve cells in the disease. Ubiquitin is the way cells designate trash that needs to be removed. The U.S. researchers led by Haining Zhu Ph.D., showed in the Journal of Biological Chemistry that when p62 is co-expressed with mutant SOD1 in lab grown cell, it enhances the abnormal deposits, yet this did not kill the cells.
http://www.ncbi.nlm.nih.gov/pubmed/17296612

Precursor to Trophic Factor Allows Astrocytes to Kill Motor Neurons

Astrocytes, the glial cells surrounding nerve cells, make and release a precursor to the helper molecule, nerve growth factor (NGF), and apparently this form of NGF can kill motor neurons. As published by researchers at New York University, the pro-NGF includes a section that can be neutralized by an appropriate antibody to counter the toxic effect. Led by Moses Chao, Ph.D., the researchers suggest in their report in Molecular and Cellular Neurosciences that the pro-NGF might serve as a therapeutic target in motor neuron disease.
http://www.ncbi.nlm.nih.gov/pubmed/17188890

Normal Human SOD1 in Excess Harms Mice

Swedish researcher P. Andreas Jonsson M.D., Ph.D., working with Stefan Marklund, M.D., and colleagues at Umeå University Hospital reported in the Journal of Neuropathology and Experimental Neurology that transgenic mice that make the human SOD1 protein in excess show similarities to mice expressing the D90A mutant of the SOD1 protein, the most common SOD1 mutation linked to inherited ALS. Both mice made more than the usual amount of SOD1 and show neuronal cell loss in the spinal cords, though the mice expressing the normal human SOD1 protein at the elevated rate showed less neuron loss, later in life, than mice making the mutant protein. Mice with just one gene coding for the D90A mutant SOD1 showed even milder alterations. The researchers suggest that normal human SOD1 might be able to cause disease if produced in excess in mice, as it does produce aggregates. They speculate as to whether in people, the normal and abundant SOD1 protein might both participate in producing ALS, especially when other factors exist that increase the risk of the disease.
http://www.ncbi.nlm.nih.gov/pubmed/17146286

Mutations Prevent Proper Folding of SOD1 Molecule

Ron Kopito, Ph.D., and colleagues at Stanford University published in The EMBO Journal that various mutations to the SOD1 molecule that produce some inherited forms of ALS prevent the proper folding of this protein. Proper folding apparently takes place without the need for the guiding molecules called chaperones and requires the tight binding of the zinc but not the copper molecule contained in the protein. Their model of the way the protein folds up after it is manufactured, generated by the study of eleven different ALS related mutations, predicts increased amount of intermediates that could produce a toxic form prone to accumulate abnormally inside cells.
http://www.ncbi.nlm.nih.gov/pubmed/17255946

New SOD1 Mutation Found

Hiroshi Mitsumoto, M.D., and colleagues at Columbia University reported a novel mutation in SOD1 that does not alter the enzyme activity. The mutation was found in a female ALS patient with no family history of the disease, according to publication in the Journal of Neurological Sciences.
http://www.ncbi.nlm.nih.gov/pubmed/17257622

ALS and Primary Lateral Sclerosis

Michael Strong, M.D., and colleagues at the London Health Sciences Centre, Ontario, Canada,  published criteria to distinguish ALS and primary lateral sclerosis in the Archives of Neurology. The two conditions can be confused if upper motor neuron symptoms appear first, yet the prognosis is better for the primary lateral sclerosis. They conclude that a patient presenting with spasticity who does not develop wasting within three years most likely does not have ALS.
http://www.ncbi.nlm.nih.gov/pubmed/17296839

Muscle Biopsy Proposed to Aid ALS Diagnosis

Researchers at Washington University in St. Louis, led by Alan Pestronk, M.D., reported in Muscle & Nerve that atrophic muscle fibers of mixed fiber types are evident in biopsy of people with ALS but not other causes of denervation. This difference was confirmed for 11 patients, 10 of whom had ALS as a final diagnosis.
http://www.ncbi.nlm.nih.gov/pubmed/17299742

Human Neural Stem Cells Make Connections in Rat Brain

Vassilis Koliatsos, M.D., and collaborators at Johns Hopkins University in Baltimore, Md., reported in Public Library of Science, Medicine that neural stem cells from human fetal spinal cord can turn into neurons and form extensive connections when placed into adult rats. These rats lack immune system components that would reject foreign tissue. But the grafting also worked similarly in normal adult rats given a drug to suppress the immune system. Location of the stem cells seemed to determine whether they adopted neuron or glia fate. Functional recovery was not investigated.
http://www.ncbi.nlm.nih.gov/pubmed/17298165

Aging, Neurodegeneration Affect Proteins That Protect Cells

The so-called heat shock proteins (Hsp) that protect cells appear to react to various neurodegenerative diseases as modeled in mice and also change as normal mice age, report investigators at Johns Hopkins University led by Michael K. Lee, Ph.D. Both Hsp25 and alpha B-crystallin increased in the protective glial cells, called astrocytes, in affected nerve tissues in mice that model ALS by the mutation to SOD1 and to mice with mutations linked to Parkinson’s disease, which also form abnormal protein deposits. The level of alphaB-crystallin increased in spinal cord as normal mice aged. The findings reported in Neurobiology of Aging suggest a role for the heat shock proteins as protectors of astrocytes in ALS.
http://www.ncbi.nlm.nih.gov/pubmed/17316906