A new cell-based model for amyotrophic lateral sclerosis (ALS) indicates that even though two genes both cause ALS, they may do so through significantly different mechanisms. The results may have important consequences for interpreting research studies and developing new therapies. The study was published in the journal Proceedings of the National Academy of Sciences.
“These findings tell us that ALS may be occurring through multiple pathways,” said ALS Association Chief Scientist Lucie Bruijn, Ph.D. “Assuming these results are confirmed by other laboratories, they should help us understand how the disease’s processes involving two genetic mutations differ and what they have in common. That will help us focus on designing drugs for each pathway and drugs for the pathways they share. Both could be important for effective treatment.”
The study examined the effects of a new ALS gene that makes a protein called TDP-43. Mutations in the TDP-43 gene are a relatively rare cause of ALS, but scientists are especially interested in it because in most forms of ALS, TDP-43 protein forms aggregates inside motor neurons, the nerve cells that die in the disease. Loss of motor neurons leads to paralysis and early death.
The study was carried out by scientists at the University of Edinburgh in Scotland led by Siddarthan Chandran, Ph.D., assisted by researchers in London led by Chris Shaw, M.D., in San Francisco led by Steve Finkbeiner, M.D., Ph.D., and in New York led by Tom Maniatis, Ph.D. Dr. Maniatis serves as Chair of The ALS Association’s Scientific Advisory Board. He has been instrumental in helping The Association shape its Translational Research Advancing Therapies for ALS (TREAT ALS™) program, through which The Association funds a diverse portfolio of research to find treatments and a cure for Lou Gehrig’s Disease.
The scientists worked with motor neurons and supportive cells, called astrocytes. Both cell types were derived from “induced pluripotent stem cells” (iPS cells), which are derived from skin cells and have become a major new source of cells for research into neurodegenerative diseases such as ALS.
They found that mutations in TDP-43 caused the death of astrocytes but were not toxic to motor neurons. This lack of motor neuron toxicity differs significantly from ALS models that use a different disease-causing gene called SOD1. In SOD1 models, motor neurons die even when the mutant gene occurs only in the astrocytes. The reasons for this difference remain unknown. It is still unclear, based on these results, what leads to motor neuron death in ALS due to TDP-43 mutation.
“We have more work to do to understand these important findings,” Dr. Bruijn said, “but these results may be telling us that a key step in the disease is loss of astrocytes. If that is true, it should open up new therapeutic targets to support these cells so they can continue to support motor neurons. The study further demonstrates the value of IPS cells in understanding disease mechanisms and developing potential screens for drug discovery.