ALS Research Briefs: SOD1, Repeat Expansions

SOD1 causes toxicity in some familial and some sporadic ALS

In some people with bulbar-onset sporadic ALS, changes to the SOD1 protein cause the same toxicity as is generated by mutated SOD1 protein in the familial (inherited) form of the disease, a team of researchers has reported.

The toxicity appears to occur when the SOD1 protein changes its shape (conformation). In familial ALS, this conformational change can be caused by mutations. In people with normal SOD1, age, environment and possibly other factors may cause similar changes. In both cases, the misshapen protein gains new functions that are toxic to the muscle-controlling nerve cells called motor neurons.

This finding suggests that SOD1 may be a "common trigger" between the two forms of the disease, the researchers wrote in an article, published online March 13, 2012, in Proceedings of the National Academy of Sciences. For more, read An Over-Oxidized form of Superoxide Dismutase Found in Sporadic Amyotrophic Lateral Sclerosis with Bulbar Onset Shares a Toxic Mechanism with Mutant SOD1.

The identification of a disease mechanism common to both mutant SOD1-linked familial ALS and a subset of bulbar-onset sporadic ALS could help researchers develop biomarkers to distinguish different types of the disease. It also could help them develop SOD1-based therapies that could benefit people with familial or sporadic ALS that's caused by changes in the SOD1 protein.

C4F6 detects mutant SOD1 in ALS-affected tissues

A monoclonal antibody called C4F6 reacts with mutant SOD1 protein present in ALS-affected tissue, a research team has reported, opening up the possibility that it can be used as a molecular tool to help scientists understand the ALS disease process, help facilitate drug screening and diagnosis, and potentially provide a target for therapy development.

In findings published online March, 19, 2012, in Proceedings of the National Academy of Science, a team of scientists reported that in mouse and rat ALS disease models, and in human tissues, the C4F6 antibody demonstrated its ability to selectively detect only motor neurons (nerve cells) affected by mutant SOD1. (A monoclonal antibody is a compound designed to stick to particular cells or biological substances.)

C4F6 did not detect normal SOD1 protein, or mutated SOD1 in unaffected tissues.

The published report, Localization of a toxic form of superoxide dismutase 1 protein to pathologically affected tissues in familial ALS is available for purchase.

MDA did not fund this project, but study team members included current MDA grantees Jean-Pierre Julien at Laval University Research Centre, Quebec; Jonathan Glass, director of the MDA/ALS Center at Emory University School of Medicine in Atlanta; and Jeffrey Rothstein, director of the MDA/ALS Center at Johns Hopkins University in Baltimore.

NIPA1 'repeat expansions' are a risk factor, disease modulator in ALS

A research team with members based in Belgium, Germany and the Netherlands has reported that a particular type of mutation called a repeat expansion mutation in the NIPA1 gene is a common risk factor for ALS and modifies disease course.

"This is the first example of a genetic variant that increases the susceptibility to the disease as well as modulating the disease onset and survival," the team reported in its findings, reported online Feb. 28, 2012, in Human Molecular Genetics. (NIPA1 Polyalanine Repeat Expansions are Associated with Amyotrophic Lateral Sclerosis is available for purchase.)

A repeat is a string of nucleotides (the bases, or building blocks, of DNA) that occurs sequentially multiple times in a given stretch of DNA. A repeat expansion occurs when an error causes the number of repeats to increase. The NIPA1 mutation is a trinucleotide repeat expansion in which a "three-letter" string of nucleotides coded GCG is repeated far more times in people with ALS than in people unaffected by the disorder.

The research team classified 2,292 people with ALS and 2,777 unaffected "controls" as having "short" (less than seven), "normal" (seven), or "long" (greater than seven) repeat lengths, and found that shorter and longer lengths were very rare in the people who comprised the control group.

The team found that long repeat expansions had a significant effect on disease susceptibility, disease duration and age of onset. In those with long repeat expansions, average survival was three months shorter than that of people with ALS whose number of repeats fell within the normal range; onset of symptoms in the group with long repeat expansions occurred 3.6 years earlier.

In 2010, the team showed that deletions in NIPA1 increase the risk of developing ALS. Other repeat expansions also have been identified as risk factors for ALS, including ATXN2 in 2010 and C9ORF72 in 2011.

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