ALS Research Roundup September-October 2010

by ALSN Staff on Wed, 2010-09-01 15:46
Article Highlights:

The latest news on ALS Research

ALS participants sought for study probing oxidative stress

Investigators conducting a large study of a cell-damaging phenomenon called “oxidative stress,” common in ALS and other degenerative diseases, are seeking 420 people in whom ALS has recently been diagnosed.

Environmental, lifestyle and psychological factors will be measured in the oxidative stress study.

Oxidative stress results from high levels of toxic byproducts of energy production inside cells. These toxic chemicals (“free radicals”) normally are present, but the body can dispose of them. However, when they’re produced in excess or when cells become unable to detoxify them, they become dangerous.

The investigators, supported by MDA and the National Institutes of Health (NIH), are seeking to understand the relationship of oxidative stress to the ALS disease process and to see whether there are factors other than the disease itself (such as environmental exposures) that may influence oxidative stress. The study is at Columbia University in New York and 11 other sites in the United States.

The researchers aim to determine whether increased oxidative stress is associated with the progression of ALS; examine the associations between oxidative stress and survival in ALS; and determine whether a variety of environmental, lifestyle and psychological factors are associated with increased levels of oxidative stress markers. They’ll also evaluate associations between lipid profiles and ALS progression, and they’ll examine possible associations between oxidative stress and distinct subtypes of ALS, such as bulbar- or spinal-onset ALS, and ALS with or without dementia.

Participants must be at least 20 years old, have experienced ALS symptoms no more than 18 months prior to study entry, have no family history of ALS, and meet other criteria. For details, contact Kate Dalton at Columbia University, at (212) 305-2027 or

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Head injury-ALS connection proposed but far from proven

A small study published online Aug. 18, 2010, in the Journal of Neuropathology and Experimental Neurology, has proposed a causative link between a type of brain injury caused by repeated head trauma (called “chronic traumatic encephalopathy,” or CTE) and the development of ALS or an ALS-like syndrome.

Ann McKee at Boston University School of Medicine coordinated a group of 16 U.S.-based investigators, who analyzed nervous system autopsy samples from 12 professional athletes. The athletes all had sustained numerous head injuries, and all had CTE. Three of them also had ALS or a syndrome resembling ALS. The researchers proposed that head injury can lead not only to CTE but also to ALS.

Although repeated head trauma is considered a possible risk factor for ALS development, the data are far from clear.

And, in any case, a study of only three people cannot be taken as definitive evidence of a link to a head injury-ALS link, noted Stan Appel, who heads the MDA/ALS Center at Methodist Neurological Institute in Houston and chairs the MDA Medical Advisory Committee.

Appel said that “it is more likely that CTE does not cause ALS, but that both are independent consequences of multiple factors.”

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ALS-causing TDP43 made toxic by stability

At least some of the mutations in the TDP43 protein that are known to lead to ALS cause the TDP43 protein to be more stable than usual and change its interactions with other cellular proteins, say researchers at the University of California-San Diego. Don Cleveland and colleagues at UCSD published the new findings in the July 27, 2010, issue of Proceedings of the National Academy of Sciences.

The investigators studied the behavior of the TDP43 protein made from a non-mutated TDP43 gene and from genes with three different mutations previously found to cause ALS in humans, by putting the normal TDP43 gene and the mutated TDP43 genes into cells in the laboratory.

All three of the mutated TDP43 proteins had longer lives in the cells than the normal protein, “suggesting that abnormal stability may be a common feature for ALS-linked TDP43 mutations,” the researchers say.

They say their findings about TDP43’s longevity were unexpected. By contrast, they note, mutations in the gene for the SOD1 protein (thought to cause about 1 to 2 percent of all human ALS cases and commonly used as a model of ALS in laboratory investigations) destabilize the SOD1 protein, although they also make it toxic.

In tests involving two of the mutated TDP43 proteins, they also found that both proteins had a greater than normal propensity to interact with a protein called FUS. Mutations in the FUS gene, which lead to abnormal FUS protein molecules, are another cause of genetic ALS. Toxic interactions of TDP43 and FUS proteins could represent a “convergence of pathogenic pathways,” the researchers say.

The evidence strongly suggests that this increased stability and the abnormal protein-protein interactions are mechanisms by which TDP43 mutations cause ALS.

If confirmed, the findings could have implications not only for the small percentage of people known to have ALS resulting from TDP43 mutation, but also for the broader spectrum of people with ALS. About 90 to 95 percent of ALS patients have the sporadic (nongenetic) form of the disease; about 5 to 10 percent have genetic (familial) ALS; and a small percentage of those have TDP43-related genetic ALS.

MDA did not fund this study. However, Cleveland has current support from MDA for ALS-related research.

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Blocking IL-1-beta improved life span of ALS mice

Elevated levels of an immune system protein called interleukin-1-beta (IL-1-beta) exacerbates physical symptoms in mice with an ALS-like disease, and blocking this protein extends survival in these mice, a research team in Germany has found. The study adds to the accumulating evidence that the immune system misbehaves in ALS and that altering its behavior could be a way to treat the disease.

Arturo Zychlinsky and colleagues at the Max Planck Institute for Infection Biology in Berlin published the findings in the July 20, 2010, issue of Proceedings of the National Academy of Sciences.

In an accompanying editorial, Jos van der Meer and Anna Simon of Radboud University Nijmegen Medical Centre in the Netherlands noted that elevated concentrations of IL-1-beta have been detected in the spinal fluid and spinal cords of ALS patients, including those with non-SOD1-related ALS.

They said a medication called anakinra is an IL-1-beta receptor blocker that has been used to treat humans, although its ability to enter the central nervous system (which may be necessary to treat ALS) is minimal. They said there are other drugs that also block IL-1-beta that have recently come on the market that could be investigated for their possible utility in ALS.

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Cytokinetics drug increases muscle force in healthy subjects

The experimental drug CK-2017357, now in a phase 2, multicenter trial at 15 U.S. sites in people with ALS, has been found to increase contractile force in a tested lower leg muscle in healthy male subjects. The orally administered drug is designed to increase the sensitivity of muscle fibers to calcium. Its developer, Cytokinetics, announced the findings July 22, 2010, calling the results “encouraging.”

Participants in the CK-2017357 ALS trial, in which two doses of the drug are being compared to a placebo, must have a body mass index (BMI) of between 18 and 30 kilograms per square meter, be able to maintain their grip for 15 seconds and meet other study criteria.

For details, contact project manager Katy Shaver at Massachusetts General Hospital at (617) 643-7434 or

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ALSN Staff
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