July Research Summary

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.

SOD1 Alteration Common to Inherited and Sporadic ALS

Researchers working with Jian Liu, Ph.D., at the California Pacific Medical Center in San Francisco, collaborating with the teams of Don Cleveland, Ph.D. and Jeff Rothstein, M.D., Ph.D., reported in the Proceedings of the National Academy of Sciences that a change in the SOD1 protein may occur in all ALS. This protein is the enzyme, copper-zinc superoxide dismutase (SOD1) first shown to be responsible, when mutated, for some inherited ALS. Yet a changed form appears in the spinal cord of ALS patients whether or not they have the mutated protein in which the gene coding for the protein is defective. The change in SOD1 protein occurred in inherited ALS and spontaneously appearing cases without a family history of the disease—but not in patients with other neurodegenerative diseases. This altered, SOD1-containing protein is thus produced not only in familial ALS caused by SOD1 mutation, but also in sporadic ALS in which the protein is genetically normal. It was revealed when the researchers added a chemical modification that specifically finds this form. This SOD1 protein change is suggesting a common marker of damage for both forms of ALS and could point to a therapeutic approach. http://www.ncbi.nlm.nih.gov

Mutant Protein Mechanism Proposed for ALS

Joan Selverstone Valentine, Ph.D., of the University of California, Los Angeles, and colleagues at the University of Florence suggested a way that the mutant protein in some forms of ALS can produce abnormal clumps inside cells when it lacks its metal ions. They studied the SOD1 protein in a cell free environment that mimics the chemistry inside cells. Taking away the metal ions from the normal protein caused it to form clumps, called aggregates. They proposed that if the mutated protein, with more than a hundred variants responsible for some cases of inherited ALS, turns out to lack its copper and zinc at some point, it would suggest a common way for all the different mutations in the SOD1 protein to produce damage. The lack of metal ions frees molecular contacts (the amino acids called cysteine) within the protein to interact with each other and form abnormal but stable interactions, key to the clumping, the researchers proposed. The study is published in the Proceedings of the National Academy of Sciences. http://www.ncbi.nlm.nih.gov

Zebrafish Model for ALS
As reported in Human Molecular Genetics, the over production of a mutant SOD1 protein results in damage to the motor neuron axons in zebrafish. Investigators working with Wim Robberecht, M.D., Ph.D., at the K.U.. Leuven, Belgium, and collaborators showed the axon damage occurs with all mutant SOD1 molecules tested. Decreasing the amount of the helper molecule, vascular endothelial growth factor (VEGF), implicated in ALS, increased the damage to axons. Increasing VEGF prevented the damage. The new model of ALS should help identify new treatments by rapid screening of candidate therapeutics. http://www.ncbi.nlm.nih.gov

Muscle Biopsy may be Useful Early in ALS
Researchers at Washington University in St. Louis, led by Alan Pestronk, M.D., studied the muscle fiber pathology in different types of motor neuron and other diseases, concluding that the pattern identified in ALS might help in diagnosing the disease.

As reported in Muscle & Nerve, a pattern of frequent atrophic groups containing mixed fiber types in a muscle biopsy should suggest a diagnosis of a motor neuron syndrome or motor neuropathy.
http://www.ncbi.nlm.nih.gov

Sensory Loss Can Occur in ALS
Two independent research groups report that ALS patients can sometimes experience loss of sensation in some nerves. Although ALS is primarily due to death of the motor neurons, the ones that contract muscles, apparently the disease can also have some effect on the ability to carry sensory information back to the spinal cord and brain, report investigators led by Nigel Leigh, M.D., Ph.D., of King's College London, and by Kirsten Pugdahl, M.D., at Aarhus University Hospital, Denmark, and a multinational team. The reports were published in the Journal of Neurology, Neurosurgery, and Psychiatry.
http://www.ncbi.nlm.nih.gov and http://www.ncbi.nlm.nih.gov

TDP-43 and Progranulin in FTD

Ian Mackenzie published in Acta Neuropathologica on the presence of the newly identified common link between ALS and a type of cognitive change, called frontotemporal dementia (FTD). This protein is also present in people who have FTD due to a progranulin mutation, he reported. Rarely, motor neuron disease is also present with progranulin mutation.
http://www.ncbi.nlm.nih.gov

SOD1 RNA Therapeutic Ferried into Brain

Harvard researchers published in Nature on a method to get into brain the relatively large molecules that can silence the genetic instructions for mutant SOD1. Protein from the rabies virus is able to carry therapeutic RNA silencing molecules across the blood brain barrier that usually excludes such large entities. They used an RNA silencing molecule targeted to the SOD1 mutant protein to demonstrate their technique. Silencing RNA is a therapeutic approach considered for some inherited ALS, as the production of the mutant protein responsible for the disease can be decreased. This new approach should add to the ability to reach the affected tissues, the brain and spinal cord, with RNA silencing therapeutics. The team, including researchers from the University of Iowa and in Korea, was led by Manjunath N. Swamy, M.D. http://www.ncbi.nlm.nih.gov