A study released online Tuesday led by researchers from the Lawrence Berkeley National Laboratory and the Scripps Research Institute proposed a cause of amyotrophic lateral sclerosis, known more commonly as ALS.
Researchers suggest that the protein superoxide dismutase, or SOD, in severe cases of ALS is less structurally stable and thus more prone to misassembly, such as clustering or aggregation.
The speed at which clustering and aggregation of SOD occurs in neurons is indicative of the severity of ALS in the patient, according to John Tainer, professor of structural biology at the research institute and a principal investigator of the research.
Because proteins communicate with each other through signals and interlocking, their structure is extremely important, Tainer said.
When one protein is more flexible and less structurally stable, it loses its shape and could result in misassembly, destroying the necessary tight fit between the two interlocking proteins.
“If you catch a ball, you might mold your hand to catch the ball, creating a tight fit,” Tainer said. “If one enzyme is more flexible, (the two) fit together in a less specific way. When they don’t keep that precise shape, they create promiscuous structures.”
He described two proteins as locking together like two puzzle pieces.
“If you make one piece of a puzzle floppy, it won’t fit with its partner,” Tainer said. “It’s like putting Mona Lisa’s arm on her face. … It doesn’t fit.”
According to the research, stabilizing SOD could be instrumental in treating or preventing SOD-linked ALS.
ALS, also known as Lou Gehrig’s disease, whose awareness was popularized by the “ice bucket challenge,” targets muscle-controlling neurons and can prove deadly when it affects neurons that control breathing. As many as 30,000 Americans are living with the disease, according to the ALS Association.
“ALS is a fatal disease with no cure and only poor options for treatment,” said Elizabeth Getzoff, a professor in the department of integrative structural and computational biology at the research institute and senior author of the research, in an email. “Greater understanding is badly needed for developing effective treatments.”
Researchers studied the mutations of the gene SOD1 and their effects on protein stability.
“If our hypothesis is correct,” said David Shin, a research scientist in Tainer’s lab, in a Berkeley Lab press release, “future therapies to treat SOD-linked ALS need not be tailored to each individual mutation—they should be applicable to all of them.”
Previous ALS research proposed various causes, while this more recent research seeks to explain not only the disease but also the mutations and differing severities of the disease, according to Tainer.
Researchers identified two of the 153 sites on the protein to investigate further. For Shin, narrowing down research to these particular locations allowed for a more thorough understanding of site-specific mutations that might lead to ALS.
“If I broke off a wheel and clogged the tailpipe of a car, people would say that they are important things, and you can’t drive the car without them,” Shin said, comparing the study of the two sites to less narrow research of the disease. “You can’t really compare what’s happening between (the parts) if you’re trying to fix the car as a whole.”
The five-year research was funded mainly by the National Institutes of Health through grants given to Tainer and Getzoff.
“We now know what to look for and how to look at it,” Tainer said. “This gives us approaches on how to fix it.”