A recent study by two Penn professors revealed a genetic risk factor for an incurable and fatal disease that affects more than 5,600 Americans each year.
Last week, Professor of Cell and Developmental Biology Aaron Gitler and Biology Professor Nancy Bonini published a study in Nature magazine that may lead to new therapies for amyotrophic lateral sclerosis, also known as Lou Gehrig’s disease. Currently, the only available treatment options delay the disease’s progression, as opposed to curing it.
Gitler began by studying yeast cells, looking for factors that could alter their levels of TDP-43, an ALS-related gene.
“If we can figure out how simple yeast cells deal with clumping proteins, that might give us insight into how complicated neurons do it,” Gitler said.
In the study, Gitler found that the ataxin 2 gene affected the strength of TDP-43 in the yeast cells. Ataxin 2 contains the amino acid glutamine which, when mutated, expands and poses a risk for ALS.
These protein expansions are larger than those in ALS-free cells, but smaller than the expansions previously studied in cells affected with another neurodegenerative disease.
Gitler and Bonini then collaborated to apply the findings to fruit flies which, unlike yeast cells, contain nervous systems. After transferring TDP-43 and ataxin 2 into the flies, the experiment yielded similar results to the yeast cells. The researchers found that higher levels of mutated ataxin 2 resulted in neurodegenerative properties of ALS within the flies. Conversely, by decreasing levels of the mutated gene, the toxicity of TDP-43 decreased.
“It’s really quite remarkable that this came from really simple genetics from organisms like yeast and flies,” Bonini said. “This is just another example where we think that these model organisms really have a lot to bring towards insight into human disease.”
In an effort to further verify the effects of the interaction between the two proteins, Gitler and Bonini collaborated with Virginia Lee and John Trojanowski, co-directors of Penn’s Center for Neurodegenerative Disease Research, in order to apply these findings to human tissue.
According to Gitler, the team used 915 DNA samples of ALS patients and 980 DNA samples of healthy individuals, and recorded the lengths of ataxin 2 glutamine expansions in each group. They found that 4.7 percent of ALS patients had the mutated ataxin 2 gene, compared to only 1.4 percent of healthy individuals.
Gitler wrote in an e-mail that the study highlighted the School of Medicine’s “major strength” of applying basic lab findings to clinical research.
Bonini hopes the “spectacular interaction” discovered between ataxin 2 and TDP-43 in yeast cells, fruit flies and human DNA samples will spark research for future therapies to combat ALS.
“I’m really cautiously optimistic that we’ve identified a new potential target that could provide the foundation for new types of therapeutics,” she said. “We’re still studying it, but the hope is that this finding will stimulate labs beyond only our own to really bring in the resources of the research community towards this question.”
