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Action Uncovered in Mutant Protein's Link to Nerve Cell Death in ALS

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Front Page

Action Uncovered in Mutant Protein's Link to Nerve Cell Death in ALS

If you had to guess the culprit protein behind a disease with an exquisite preference for killing only motor neurons--which number a mere 300,000 among the hundreds of millions of neurons in the human brain--simple deduction would make the prime suspects some idiosyncratic set of proteins unique to those cells.

After eleven years of searching, Robert Brown, Piera Pasinelli and associates have hunted down the mechanism by which mutant SOD1 proteins may cause some cases of Lou Gehrig's disease. (Photo by Steve Gilbert)

SOD1 constitutes one half of one percent of all cytosolic protein and, "in the high oxygen environment that is our Earth, it's fundamentally important to how we survive," said Brown, HMS associate professor of medicine at MGH and director of the hospital's Day Neuromuscular Research Laboratory. But even good proteins can go bad. In any of its approximately 100 mutant forms, SOD1 becomes a toxin mysteriously linked to the root cause of many ALS cases. For more than a decade, researchers have been trying to figure out this mutant's modus operandi.

Now, Day lab research headed by Brown and HMS neuroscientist Piera Pasinelli has shown that the malformed proteins kill by targeting mitochondria with the help of an unwitting ally: the anti-apoptotic protein Bcl-2. The revelation, published in the July 8 Neuron, may give researchers their first clues as to how mutant SOD1 causes toxicity and why the ubiquitous protein selectively afflicts motor neurons.

Mobbing Mitochondria

"This is the strongest evidence that we've seen that mutant SOD1 directly interferes with an apoptotic pathway."

"The idea behind this type of toxicity is that instead of being a loss of function for SOD1, the mutant form actually adapts its own novel way of functioning," Pasinelli said. "This is the strongest evidence that we've seen that mutant SOD1 directly interferes with an apoptotic pathway."

The researchers hypothesize that SOD1-driven toxicity can play out in either of two ways: Bcl-2 may be a hostage or an accomplice.

In the first scenario, as the clumps soak up more and more of the antioxidant and anti-apoptotic proteins, the cells simply become increasingly susceptible to pro-apoptotic stress. For example, analysis of the aggregates shows that the bound Bcl-2 is not capable of trapping the apoptotic protein Bax.

The second scenario holds that Bcl-2 may itself turn pro-apoptotic when it links up with the mutant protein. Recently published research from the Burnham Institute in La Jolla, Calif., shows that Bcl-2 shifts into a form that is damaging to the outer mitochondrial membrane when the protein is exposed to certain nuclear receptors. A similar transformation might come into play when Bcl-2 becomes entangled in the SOD1 clumps.

Another variation of this scenario relates to Bcl-2's secondary function as a regulator of mitochondrial membrane potentials. When the aggregates meet with a mitochondrial membrane, the bound Bcl-2 may clog up the same chemical pathways that it normally keeps in check.

There is reason to believe that the second scenario may be more significant than the first. Along with spinal tissue, the HMS researchers examined the liver cells from the mice and human subjects. The cells, which possess levels of mutant SOD1 just as high as their neuron counterparts, showed no protein aggregates. This may hint that the mutant SOD1's selective effect upon motor neurons may be linked to the damage it inflicts with the aid of Bcl-2 in aggregate form.

The Open Question

Whatever the actual mechanism, the findings must be viewed from the perspective that SOD1 mutations are linked clearly to only three percent of all ALS cases. The vast majority of patients do not have any known genetic basis for their disease. Still, SOD1 mutations remain the only determinable cause of ALS.

"The fact is that there is a lot of pathology that overlaps between SOD1 ALS and the sporadic form," Brown said. And that overlap can be instructive.

It was recently discovered, for example, that the inflammation enzyme cycloxygenase is present in very high quantities in mice with mutant SOD1. Upon further investigation, this was found to be true in all cases of human ALS. In October, results will be released for an MGH clinical trial testing whether or not the arthritis drug celecoxib (Celebrex), which inhibits this enzyme, can stave off the effects of ALS in humans in the same way it does with mutant SOD1 mice.

"Will this Bcl-2 interaction be such an overlapping element? We don't know yet," Brown said. "The research has been full of surprising twists. It's hard to predict what will happen next."

--Stu Hutson