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doi: 10.1097/01.NT.0000360716.38820.31

ARTICLE IN BRIEF A new study strengthens the case that protein aggregation is an intrinsic part of the disease process in ALS patients with SOD1 mutations.

Disease progresses faster in amyotrophic lateral sclerosis (ALS) patients whose mutated superoxide dismutase (SOD1) protein aggregates faster, according to a new study published online May 30 in advance of the print edition of the journal Human Molecular Genetics.

The results strengthen the case that protein aggregation is an intrinsic part of the disease process in ALS patients with SOD1 mutations, and support the rationale for treatments that interrupt aggregation, including arimoclomol, which is currently being tested in ALS patients with inherited SOD1 mutations.

About 2 percent of all ALS cases are caused by SOD1 mutations; 146 mutations have been described so far. Both symptom-onset and duration vary with different mutations. No pattern has emerged to connect specific mutations to early versus later onset. But different mutations are associated with large differences in the duration of symptoms — for instance, most patients with the A4V mutation — which changes an alanine to a valine at position 4 of the protein — die within two years of onset, while those with the G37R (changing a glycine to an arginine at position 37) live more than 15 years.

Accumulation of mutant protein is a common feature of neurodegenerative diseases, including ALS, Alzheimer disease, Parkinson disease, and Huntington disease. Controversy remains whether these protein aggregates are part of the problem, contributing directly to disease pathogenesis, or conversely, whether they may be part of the solution, sequestering useless proteins the cell cannot degrade. But what is certain is that mutation of SOD1 causes it to aggregate, both in patients and in disease models.

These data led David Borchelt, PhD, professor of neuroscience at the University of Florida College of Medicine in Gainesville, and Mercedes Prudencio, a graduate student in Dr. Borchelt's laboratory, to ask two questions: Do differences in aggregation propensity among the different mutants correlate with disease progression in patients? And what property of the protein is changed by mutation that could account for the differences in aggregation?

To answer these questions, they examined the rate of aggregation of 21 mutant proteins expressed in cell culture. “There was no single characteristic to explain differences in aggregation,” Ms. Prudencio said; neither mutation-induced differences in overall electrical charge of the protein, nor the location of the altered amino acid, nor its effect on protein stability, correlated with aggregation differences.

But a clear pattern did emerge when they compared the rate of aggregation to the rate of symptom progression. “In general, there is an inverse relationship between high aggregation propensity and disease duration,” Prudencio told Neurology Today.

Mutations with the highest rate of aggregation were associated with the fastest progression, with most patients surviving four years or less with most of these mutations. Mutations with a moderate rate of aggregation were associated with longer survival. However, she noted, the association broke down for mutations with the slowest rate of aggregation — survival was too variable among this group, making them “essentially unpredictable.”

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“In all we now know about ALS, we have two different processes going on,” Dr. Borchelt said. “There is a toxic property of the mutant protein that initiates the disease — we don't know what that is yet,” though some evidence suggests that it may involve several copies of the mutant protein associating with one another. “Then, once the disease is established, another process affects its rate of progression,” he continued. “This differs from one mutant to the other. That period seems to be where aggregation plays a role.”

But are the aggregates themselves toxic? “The fact that we see aggregation as a risk factor for progression leads me to believe that aggregates could be toxic in some way. Our data would say they probably are, but it is possible aggregation is a correlation with something else,” such that whatever toxic property accelerates disease progression also accelerates aggregation, he said.

Testing that is the next step. Dr. Borchelt will be looking for ways to slow aggregation in a model system, to see if that reduces toxicity in the cell.

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Meanwhile, a placebo-controlled trial has begun to determine if an aggregate-disrupting drug can slow disease progression in ALS patients with SOD1 mutations.

According to lead investigator Michael Benatar, MD, associate professor of neurology and co-directory of the Muscular Dystrophy Association Clinic at Emory University, arimoclomol (developed by CytRx Corporation in Los Angeles) is one of the few drugs under investigation that decreases SOD1 aggregation. It does so by activating heat shock proteins, which aid the cell in processing misfolded proteins as part of the overall protein quality control system.

“I think the results about aggregation and disease progression are interesting,” Dr. Benatar said. “ALS is probably a multifactorial disease. These data add weight to the relevance of aggregation as part of the process, although I think the authors were appropriately cautious about the opposite argument,” that aggregates are more like bystanders than contributors to the disease.

A major problem in research on ALS and other neurodegenerative diseases is the weak correlation between results in cell and animal models and results in patients. Dr. Benatar said his analysis of the ALS mouse literature led him to conclude that “the data are quite poor, and that there is tremendous publication bias, with negative results not being published.”

An additional problem has been that most drugs tried in mice are given before disease onset, rather than once symptoms appear, making the relevance of even a successful result questionable.

“We ultimately settled on arimoclomol because it showed an effect on survival in mice when given after disease onset. But we still recognize we are basing this on a very flawed literature,” he said.

Because the preclinical success of arimoclomol was in mice with SOD1 mutations, and because the disease process in sporadic ALS may not be the same as for SOD1-caused ALS, Dr. Benatar's trial is restricted to patients with SOD1 mutations, specifically those with the fast-progressing A4V mutation. He hopes this will give the highest chance of replicating the good results seen in the mice.

“The real challenge will be recruitment,” he said. He calculates there are only about 100 new cases of A4V ALS every year in the US, and he hopes to eventually recruit approximately 50 patients. “That's pretty ambitious.”

The trial is taking advantage of the resources from consortium of 80 ALS researchers, “but we are still looking for patients.” He is encouraging neurologists who may have appropriate patients to contact him at Genetic testing is being done as part of the trial.

“A successful trial could radically change what happens to patients when they get to the clinic,” he said. Currently, few patients receive genetic testing at diagnosis because of the lack of meaningful treatment options based on genetic status. But should the treatment be effective, that would change.

“It also has the potential to change what happens to patients with sporadic ALS,” since a small portion of them — perhaps up to 2 percent — also have SOD1 mutations, Dr. Benatar said.

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• Prudencio M, Hart PJ, Andersen PM, et al. Variation in aggregation propensities among ALS-associated variants of SOD1: Correlation to human disease. Hum Mol Genet 2009; E-pub 2009 May 30.
    ©2009 American Academy of Neurology