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.
TDP-43 Protein’s Possible Role in ALS
Canadian ALS researcher Michael Strong, M.D., of the Robarts Research Institute at the University of Western Ontario in London, published evidence that the protein TDP-43, newly implicated in both ALS and a type of cognitive change, interacts with the supporting framework within the long fiber of motor neurons, called the neurofilaments. TDP-43 stabilizes the messenger RNA that codes for production of the low molecular weight neurofilament. Strong suggested that the interaction might prompt formation of abnormal deposits of protein within the nerve cell. If confirmed, this would suggest that TDP-43 might affect the processes by which the nerve cell maintains its flow of supplies. The report appears in Molecular and Cellular Neuroscience.
Criteria on how to classify the brain diseases called frontotemporal dementia (FTD) are published in Acta Neuropathologica. The molecular and cellular findings on autopsy will help investigators understand diverse or common processes behind the behavioral and cognitive changes in the diseases, which can appear to different degrees in ALS. The international team of researchers collaborating on these proposed criteria to diagnose FTD worked with Nigel J. Cairns, Ph.D., at Washington University in St. Louis, Mo.
TDP-43 as Distinct Molecular Sign of Motor Neuron Disease
The presence of TDP-43 can be considered a specific marker of ALS concluded Mayo Clinic, Rochester, Minn., investigators working with Keith Josephs, M.D., as reported in Acta Neuropathologica. Presence of TDP-43 in abnormal deposits brain suggests that motor neuron disease is present whether or not symptoms appear, the investigators concluded.
The conclusion that presence of TDP-43 is a unifying theme in frontotemporal dementias was endorsed by an independent collaboration led by Ian Mackenzie, M.D., Vancouver General Hospital, Canada, published in the American Journal of Pathology.
At the conference this month in Canada on FTD, pathologists attending the meeting debated the presence of TDP-43 in abnormal deposits as a basis for diagnosis of ALS with cognitive change. Please watch for a report on the meeting to be posted soon at www.alsa.org.
Different Genes Active in Different FTDs: Microarray Data
Eileen Bigio, M.D., Northwestern University, Chicago, and collaborators published in Acta Neuropathologica a microarray analysis of genes differentially active in FTD with and without motor neuron involvement. With human autopsy brain samples, they found that FTD and controls differ in more than 100 molecular pathways. Changes appeared in proteins that manage connections among nerve cells and the cell trash disposal system, called the proteasome, as well as transport within cells and the cell death pathway called apoptosis. The investigators validated three genes so far as having different expression levels, including a component of the molecular motor, dynein, and a packaging protein, called annexin A2 that helps move materials within cells. Progranulin and TDP-43 also showed changes in their gene expression in some of the cases.
Nuclear Reprogramming: Progress Toward Drug Discovery
Research reported in Nature by Harvard investigator Kevin Eggan, Ph.D., and colleagues suggest that it may be possible to use previously fertilized egg cells to produce disease- specific stem cell lines using somatic cell nuclear transfer. Prior efforts at nuclear reprogramming have relied on eggs which have proven difficult to obtain. Instead it may be possible to use cells left over from in-vitro fertilization to generate stem cells that carry the genes responsible for disease such as ALS. The researchers were able to use fertilized eggs that would routinely be discarded because they carry too many chromosomes to develop normally.
Another paper in Nature, by a group working with Rudolf Jaenisch, Ph.D., at the Whitehead Institute, suggests an additional alternate route toward nuclear reprogramming. The cells called fibroblasts that give rise to connective tissue such as cartilage can be given genes that allow them to revert to a more primitive state, quite similar to if not identical to stem cells. If these gene treated fibroblasts could be made from adult patient skin cells, they might yield stem cells that reflect the genetics of the disease state in ALS.
Researchers at Kyoto University also are making progress on nuclear reprogramming. They orchestrated a return toward pluripotency—the ability to form any type of cell, the hallmark of a stem cell— by turning on genes that produce four key proteins: Oct4, Sox2, c-Myc and Klf4. They used a disabled virus to bring in these four genes. An earlier report by this group, led by Shinya Yamanaka, M.D., Ph.D., had not shown enough of a shift toward stem cell properties. They now do so and call their cells induced pluripotent stem cells, or iPS cells. Their findings were also published in Nature.
Stanford researchers working with Gary Steinberg, M.D., Ph.D., reported in the Proceedings of the National Academy of Sciences that human stem cells tagged with magnetic nanoparticles can be followed by imaging. The cells appear unaffected by the tagging and integrate as expected when transplanted into newborn or injured rodent brains. This tagging might allow researchers to better understand how to use stem cells as therapy.
ALS Progression Slows in Early Stages with Exercise
A study in Neurology suggests that the early stages of ALS may be prolonged by moderate exercise. Patients that practiced strengthening exercises using weights three times a week appeared to maintain function and retain quality of life. Eight of the 13 people assigned to the weight training completed the six month study, as did ten of the 14 who did only stretching exercises. Function declined 12 percent less rapidly in the weight training group, and quality of life declined 16 percent less rapidly, according to the investigators working with Vanina Dal Bello-Haas, Ph.D., at the University of Saskatchewan, in Saskatoon, Canada, and Hiroshi Mitsumoto, M.D., at Columbia University in New York City. Findings need to be replicated in a larger group to make a definitive statement about the value of exercise in ALS.
Three British friends who played competitive amateur soccer developed ALS at about the same time, according to report investigators collaborating with Ammar Al-Chalabi, Ph.D., at King’s College, London, U.K. The investigators, publishing the finding in Amyotrophic Lateral Sclerosis, suggest that intense exercise might be involved in the disease.
Defect in DNA Repair Associates with ALS Risk for Men
Italian researchers led by Gabriele Siciliano, M.D., at the University of Pisa published in Neuroscience Letters on a possible link to increased risk of ALS in men with a variant of a gene involved in repairing damage to DNA.
Japanese investigators working with Koji Abe, M.D., Ph.D., at Okayama University reported in Internal Medicine (Tokyo) two people who had a motor disorder called ataxia and who also had motor neuron disease signs. Many ataxias exist, some with known gene defects. Sometimes there is coincident motor neuron disease resembling aspects of ALS in people with ataxia (the term ataxia refers to abnormal gait, a disturbance usually due to problems in the brain area called the cerebellum). Common disease mechanisms might lead to effective treatment of both conditions.
Defenses Against Oxidative Damage Affected in Mice Modeling ALS
Abe and colleagues at Okayama University reported in Brain Research on specific enzymes in mitochondria that guard against oxidative damage, finding a decrease in mice with mutant SOD1.
Jeff Johnson and colleagues at the Waisman Center, University of Wisconsin, Madison, published online in Experimental Neurology on the role of the cellular defense system in ALS. Abbreviated ARE, this anti-oxidant response element system, when activated, prods cells to make an array of materials that defend against oxidative stress. Such stressors include potentially toxic byproducts of normal metabolism as well as external threats such as radiation and chemicals. In mice that produce mutant human copper-zinc superoxide dismutase (SOD1), ARE is activated early in the disease, by 30 days of age, in muscle. This activation then proceeds up the nerve fibers. This finding adds to controversy over the role of muscle in ALS.
Defective Transport in Nerve Fibers Responds in SOD1 Mice
A company called KineMed Inc, in Emeryville, Calif., published findings on a compound that works in mice to fix defects in the transport within nerve fibers that are affected early in the mouse model of ALS. As reported in the Journal of Biochemistry, the compound prolonged survival by a quarter and delayed onset, with a return toward normal of the dynamics of transport involving the proteins called microtubules that maintain traffic along the nerve fibers. The researchers led by Marc Hellerstein, M.D., Ph.D., propose the microtubule dynamics as a biomarker of the disease and a target for therapeutics.
Brain Barrier Breached in ALS?
Svitlana Garbuzova-Davis, Ph.D., and colleagues at the University of South Florida, Tampa, reported in Brain Research that the barrier between the brain and spinal cord and the rest of the body that helps regulate the function of the brain and protects it from disturbance may be disrupted in ALS. This breach was evident in SOD1 mutant mice in areas of motor neuron degeneration at both early and late stages of disease. Capillary rupture was observed in brainstem in early symptomatic mice. Investigation of the structure of the capillary vessels revealed damage to the endothelial cell membrane and/or basement membrane followed by vascular leakage.
Researchers at Harvard and MIT led by Li-Huei Tsai, Ph.D., published in the EMBO Journal that a metabolic pathway involving the sirtuin family of histone deacetylases may be involved in aging and in the disease process in ALS and other diseases of aging. A molecule abbreviated as SIRT1 is produced in increased amounts in mouse models for Alzheimer’s, ALS and in neurons growing in the lab that are challenged with toxic insults. This pathway is under investigation for ALS therapeutic discovery.
Retrovirus Marker Detected in ALS Patients
A report in Neurology is the third to show that reverse transcriptase occurs more often in ALS patients than in controls. The presence of this retrovirus protein in a study by Steve Scelsa, M.D., and colleagues at Beth Israel, New York City, confirms earlier reports but does not prove that a retrovirus is responsible for the disease. Some people without ALS have the marker as well. A trial of indinavir, an anti-retroviral drug, failed to help patients with ALS.
VAPB Mutation Not Linked with ALS in U.K.
Researchers working with Pamela Shaw, M.D., University of Sheffield, reported in Neurology that VAPB mutation is not found in patients whose ALS is the first in their families, at least in the U.K. This mutation in the gene coding for the protein (the abbreviation stands for vesicle-associated membrane protein-associated protein B) was reported in a Brazilian family with ALS cases and traced to a common ancestor from the time of contact with Portugal. Italians also appear to lack this mutation link with ALS.
Role of the VAPB Mutation Clarified
Brazilian researchers working with Mayana Zatz, Ph.D., at the University of São Paulo have studied the responsible VAPB gene domain for the analysis of its interactions with other cellular proteins. Findings suggest that the mutation may lead to a less stable interaction of this endoplasmic reticulum protein with at least two other proteins: tubulin and GAPDH. These two proteins have been previously related to other forms of neurodegenerative diseases and are potential key points to understand the biology and at which to aim therapeutics.
Mouse with Different SOD1 Mutation Progresses Slowly
A mouse with the mutation to SOD1 of H46R progresses very slowly as do people with this particular mutation, surviving about 15 years. The mice, as published by Japanese investigators in the Journal of Neuropathology and Experimental Neurology, show aggregates in cells and loss of nerve fibers in the spinal cord early on, and symptoms appear at around 20 weeks. Damage appears to affect other cells besides the motor neurons in this mouse.
A high resolution structure of human SOD1 with all of its metal molecules, along with molecular dynamics analyzed by computer, reveal the first stages of misfolding caused by metal deletion as reported by British researcher Samar Hasnain, Ph.D., and colleagues at the Daresbury Laboratory in Proceedings of the National Academy of Sciences.
Bone Marrow Stem Cells Explored as ALS Therapy
Italian researchers published in the Journal of the Neurological Sciences an exploratory trial in a few ALS patients of using their own stem cells collected from bone marrow as therapy. These stem cells do not appear to differ from those collected from healthy people. Of the nine ALS patients who received spinal injection (chest level) of their own mesenchymal stem cells, four appeared to have a decelerated decline in forced vital capacity (a breathing measure) and in the ALS rating scale, called the ALS-FRS. No change in spinal cord volume or in any other measures to detect possible tumors appeared during the four years of follow up. The findings will need to be explored in a larger patient trial. It is possible that the patients may have progressed more slowly as a natural feature of their disease. The appropriate controls will need to be included to see if the treatment does have effect. The researchers were working with Letizia Mazzini, M.D., at the University of Novara. These particular stem cells may counter inflammation.
Gene Therapy Promising in Parkinson’s Disease
A Phase I safety study of 11 men and one woman with Parkinson’s disease in which surgeons injected a gene-bearing virus into the brain was safe and resulted in improved motor function for Parkinson's patients during the course of one year. The findings, published in the The Lancet by Michael Kaplitt, M.D., New York-Presbyterian Hospital/Weill Cornell Medical Center, and collaborators, will need to be validated in a larger trial. Studies are underway to determine the feasibility of gene therapy approaches for ALS to alter disease progression.
