Academics and Research / Magazine Feature

Professor searches for ALS treatments

The process of discovering the etiology of a disease like amyotrophic lateral sclerosis or ALS (Lou Gehrig’s disease) follows the narrative arc of a mystery: There’s a dire problem, clues, red herrings, villains and plot twists.

In Dan Linseman’s lab, the most recent villain to emerge even has a name worthy of the neurodegenerative mischief it apparently causes: Hara-kiri, a member of the Bcl-2 protein family.

Linseman, an assistant professor in DU’s Department of Biological Sciences and senior scientist with the Eleanor Roosevelt Institute, and the 14 or so PhD, master’s and undergraduate students he supervises, are searching for targets pharmaceutical companies can attack in the treatment of neurodegenerative diseases, particularly genetic ALS.

Although Linseman’s research has focused on Parkinson’s in the past, he has shifted the priorities of his lab to study the underlying mechanisms of amyotrophic lateral sclerosis. It’s not that Parkinson’s isn’t a terrible disease,” he explains, “but Parkinson’s at least has some palliative therapies. That’s not true for ALS [there’s only one minimally productive drug]. It hits in the prime of life, when people are in their most productive years with established families. And it’s a death sentence. It’s a horribly degenerative disease.”

When ALS strikes, it attacks the motor neurons in the brain and spinal cord, making it impossible for the brain to control muscle movement. Ultimately this leads to paralysis and death. According to the ALS Association, about 30,000 people in the United States have the disease.

Largely funded by grants from the National Institutes of Health and the Department of Veterans Affairs, Linseman’s investigative team concentrates its work on the study of a specific form of cell death called apoptosis (pronounced a-puh-toe-sis), which is a kind of programmed cell suicide that afflicts motor neurons in ALS patients.

What happens is this: The cell structure responsible for making energy — the mitochondria — when under oxidative stress (assaulted by free radicals) releases certain proteins, which cause the motor neuron cell to do itself in.

“If we can figure out what proteins are involved [in causing cells to shut down], those might be targets for therapy,” Linseman says.

The mystery of ALS-related apoptosis recently took a new turn in Linseman’s lab, when Anna Andrianakos, who just completed her master’s thesis, stumbled on three protein culprits from the notorious Bcl-2 family, which may directly influence the ALS disease process.

Andrianakos was studying a group of proteins in motor neurons when she stumbled on their presence in astrocytes—the gangly, star-shaped neighbor cells responsible for keeping motor neurons healthy. Although scientists understand that when genetic ALS is present, astrocytes go haywire, releasing toxins that harm motor neurons, Andrianakos found that three Bcl-2 proteins, including Hara-kiri, are somehow involved in changing an astrocytes’ essential character from good to bad.

“One of those Bcl-2 proteins—Hara-kiri—has never been implicated in genetic ALS,” Linseman says. “We were looking in the motor neurons [for the proteins], but we found them in the astrocytes.”

An exciting finding such as this raises more questions: How is Hara-kiri turned on in the astrocytes? And what is it doing to make the astrocytes release toxins? Answers to these questions may shed additional light on the mystery of the disease and lead to better treatments.

“Our job is to identify therapeutic targets for various diseases,” Linseman says. “We are putting together pathways and learning which proteins are involved so the drug companies can design novel therapies.”

Comments are closed.