From: Roberta Friedman, PhD,
ALSA Research Department Information Coordinator

Findings published by ALSA-funded investigators in the October 10 issue of the Journal of Cell Biology have shed new light on why ALS (amyotrophic lateral sclerosis, also called Lou Gehrig’s disease) kills cells and what might be done to stop the process.

Two different mutations of the protein altered in some inherited forms of ALS can kill cells growing in culture. The reason appears to be production of a network of aggregated protein that traps other vital cell components, leaving the cell unable to “handle its trash.”

Northwestern University researcher Richard Morimoto, Ph.D., and colleagues engineered cells to express one or the other of the mutated copper-zinc superoxide dismutase (SOD1) genes. Many different mutations in the gene are associated with ALS, and mice engineered with these mutated genes show symptoms quite similar to the human disease.

Lucie Bruijn, Ph.D., science director, commented, “There has been a great deal of controversy as to the role of aggregates in ALS. Dr. Morimoto’s detailed studies looking at aggregate formation and associated proteins in real time provide compelling evidence that they are integral to the cell death process.”

Morimoto said, “Our studies may help us to better understand the course of events in neuronal cells expressing mutated SOD1 and the relationships that exist between this unusual class of aggregate structures and cell death.”

Each type of the mutated SOD1 formed so called aggregates within the lab grown cells, sticking together rather than dispersing freely within the cell. The researchers could infer the aggregates by visualizing the cells through a microscope. The investigators had designed the mutated enzyme to carry a molecular tag that glows under fluorescent light.

They could see that other small proteins move freely. But larger ones, especially the so called proteasomes that attempt to refold defective protein, and failing that, trash it, are trapped in the mesh of aggregated, mutated SOD1.

Cells that visibly formed SOD1 aggregates viewed by time lapse photography died within a day.

These cellular details should lead to insight as to how to interrupt the disease process in ALS, even for those without a family history. SOD1 mutations are linked to a few cases of sporadic disease. It is possible, for perhaps different root causes, that all ALS ends up interfering with the way cells handle their metabolic byproducts and whether they can refold damaged protein.

Certain drugs exist or are being designed that either boost the performance of the proteasome or interrupt aggregates. ALSA funded studies will continue to explore how aggregates may do damage in ALS and how to help ailing cells counteract that damage.