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Researchers: Animal Models Help Shed Light On Reduction of Toxicity in ALS

alsflyWhile working with a fruit fly model of amyotrophic lateral sclerosis (ALS), researchers at the University Pennsylvania reportedly found a method that reduces disease toxicity by slowing the dysfunction of neurons. A news release from the university states that the researchers have also shown that a parallel mechanism can reduce toxicity in mammalian cells as well.

During the study, Nancy M. Bonini, PhD, professor in the department of Biology in Penn’s School of Arts and Sciences, served as senior author. Bonini points out in the release, that, “There’s been an explosion over the last 5-plus years in the identification of genes that contribute to genetically inherited ALS.”

According to the release, prior work conducted by Bonini and other colleagues, including Aaron D. Gitler, PhD, of Stanford University, one of the researchers that Bonini worked with on the recent study, indicates that the genes TDP-43 and ataxin-2 interact. Based upon the interactions between the genes, and additional findings suggesting a link between ataxin-2 with ALS, the team continued to assess the interaction.

The non-mammalian models are faster and simpler, Bonini explains, they allow researchers to focus on conserved pathways and, “can be remarkably powerful for giving us insight into pathways involved in disease,” Bonini says.

The release notes that the team first used a yeast and fruit fly model. The results indicate that genes that modulate the cellular structures stress granules modify TDP-43 toxicity. Upon investigating fruit flies engineered to express the human version of TDP-43, the researchers state that the flies exhibited signs of a build-up of stress grandule components; this the researchers say, was evidenced by an increase in the tagging of a molecule called elF2α with a phosphate group.

The flies also exhibited symptoms reflective of ALS, as they were unable to climb as readily as normal flies and had shorter lifespans. However, by altering the expression of genes linked to elF2α phosphorylation and stress granules, researchers say, they were able to modulate these symptoms. The team also used transgenic flies to pinpoint a region of the ataxin-2 protein, key for increasing the detrimental effects of TDP-43. The researchers then went back to the fly to determine if they could reverse the TDP-43 toxicity.

They accomplished this by feeding the flies a compound designed to inhibit the addition of phosphate groups to elF2α. Upon feeding the compound to the flies, the researchers say they observed a restoration of physical strength in flies expressing TDP-43. The flies that received the compound reportedly retained more climbing ability when compared to animals without the compound.

The same compound was tested in mammalian cells. The researchers state they exposed rat neuron cells expressing TD-43 in culture to the compound, and report that it reduced the risk of cell death. The data suggests, the researchers add, that the prolonged stress state linked to stress granules and the deleterious impact on cellular pathways associated with such prolonged stress are key in the disease.

Bonini emphasizes that the results may hold promise for future treatment strategies for ALS, calling the integration of systems such as yeast, fly, and mammalian culture, “important pieces of the puzzle.”

Photo Caption: Dense protein aggregations in the motor neurons of ALS patients suggest a possible mechanism of disease.

Photo Credit: University of Pennsylvania

Source: University of Pennsylvania