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Quest for molecular cause of ALS points fingers at protein transport, say Stanford researchers

Amyotrophic lateral sclerosis, or ALS, is a progressive, fatal neurodegenerative disease made famous by Lou Gehrig, who was diagnosed with the disorder in 1939. Although it can be inherited among families, ALS more often occurs sporadically. Researchers have tried for years to identify genetic mutations associated with the disease, as well as the molecular underpinnings of the loss of functioning neurons that gradually leaves sufferers unable to move, speak or even breathe.

We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions

Now Stanford geneticist Aaron Gitler, PhD, and postdoctoral scholar Ana Jovicic, PhD, have investigated how a recently identified mutation in a gene called C9orf72  may cause neurons to degenerate. In particular, a repeated sequence of six nucleotides in C9orf72 is associated with the development of ALS and another, similar disorder called frontotemporal dementia. They published their results today in Nature Neuroscience.

As Gitler explained in our release:

Healthy people have two to five repeats of this six-nucleotide pattern. But in some people, this region is expanded into hundreds or thousands of copies. This mutation is found in about 40 to 60 percent of ALS inherited within families and in about 10 percent of all ALS cases. This is by far the most common cause of ALS, so everyone has been trying to figure out how this expansion of the repeat contributes to the disease.

Gitler and Jovicic turned to a slightly unusual, but uncommonly useful, model organism to study the effect of this expanded repeat:

Previous research has shown that proteins made from the expanded section of nucleotides are toxic to fruit fly and mammalian cells and trigger neurodegeneration in animal models. However, it’s not been clear why. Gitler and Jovicic used a yeast-based system to understand what happens in these cells. Although yeast are a single-celled organism without nerves, Gitler has shown that, because they share many molecular pathways with more-complex organisms, they can be used to model some aspects of neuronal disease.

Using a variety of yeast-biology techniques, Jovicic was able to identify several genes that modulated the toxicity of the proteins. Many of those are known to be involved in some way in shepherding proteins in and out of a cell's nucleus. They then created neurons from skin samples from people with and without the expanded repeat. Those with the expanded repeat, they found, often had a protein normally found in the nucleus hanging out instead in the cell's cytoplasm.

Jovicic and Gitler's findings are reinforced by those of two other research groups, who will publish their results in Nature tomorrow. Those groups used different model organisms, but came to the same conclusions, suggesting that the researchers may be close to cracking the molecular code for this devastating disease.

As Jovicic told me, "Neurodegenerative diseases are very complicated. They likely occur as a result of a defect or defects in basic biology, which is conserved among many distantly related species. We hope that our research may one day lead to new potential therapies for these devastating, progressive conditions."

Previously: Stanford researchers provide insights into how human neurons control muscle movement, Researchers pinpoint genetic suspects in ALS and In Stanford/Gladstone study, yeast genetics further ALS research

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