The Aggregate Dilemma: Too Obvious to Ignore

David Borchelt hunts for a novel protein.

It’s like walking into your living room and finding a llama placidly chewing a sofa cushion, this dilemma that faces ALS researchers. For years, scientists have noted obvious clumps of protein in motor neurons of patients with both sporadic and inherited forms of ALS—those who have a mutated gene for the SOD1 enzyme. The clumping also appears in motor neurons of animal models of ALS. But—the dilemma—little is known about something so obvious. How did the protein get there? What does it do? Does it cause the disease or is it part of cells’ attempts to cope with wayward metabolism? And at the most basic level, what, exactly, is the protein?

Center researchers are keen to explain the aggregates, largely because of the role they apparently play in other major neurodegenerative diseases. In Alzheimer’s disease, for example, accumulations of tau protein may contribute to tissue damage and brain-cell death. Patients with Parkinson’s disease have masses of synuclein protein in brain cells.

With ALS, the link between aggregates and disease is more murky, although Center neuroscientists David Borchelt and Jeffrey Elliott say it’s surely there. Complexes consisting largely of mutant SOD1 protein appear whenever animal models carry the disease-making mutations, both researchers have found. Recently, Borchelt’s made use of a technique to filter the complexes from a slurry of ground-up motor neurons. He’s shown a tie between ALS symptoms and amount of mutant protein: the more of it built up in an animal’s neurons, the sicker the animal.

Jeffrey Elliott at this year’s ALS Symposium.

“We’re also trying hard to purify what’s in the aggregates,” Borchelt adds. So far, SOD1 forms the lion’s share, but other as-yet unidentified proteins may exist. “Perhaps multiple proteins accumulate in people with ALS.” Recently, his team has turned to the far more common sporadic ALS (sALS), believing aggregates may play a part there as well. “In a perfect world,” he says, “we’d find a new protein aggregated in these ALS patients, one that does the same thing in the familial form.” So Borchelt’s searching widely for potential proteins, collecting samples to analyze from hundreds of sALS patients.

While both Borchelt and Elliott seek to understand the tie between SOD1 mutations and aggregates, Elliott hopes to learn if the aggregates are truly what’s toxic to motor neurons or if the problem lies with another aspect of the SOD1 protein. To do that, he’s first nailing down which mutations prompt aggregation. So far, he’s engineered an SOD1 gene with several of the mutations that appear in people with familial ALS, inserting the gene into cells in culture. Not surprisingly, the mutations triggered aggregate masses you could trip over.

Now, Elliott reports he’s much closer to his “holy grail”: an SOD1 mutation that doesn’t trigger aggregates. Will it still give mice motor neuron disease? His upcoming animal studies will go a long way to tell if the protein clumps are good, bad or indifferent.

Center scientists have their fingers crossed for such a clear picture; with such an obvious target as aggregates, says Borchelt, therapy might edge within grasp.

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