No one fully understands what causes amyotrophic lateral sclerosis (ALS), the illness commonly known as Lou Gehrig’s disease. The ailment typically crops up spontaneously, leading to dysfunction and death of motor neurons, slowly sapping strength until those living with the disease can become entirely paralyzed.
There is a desperate need for drugs to effectively halt the progression of ALS.
With an eye toward finding ALS therapies, Nancy Bonini, a professor in the Department of Biology in the School of Arts & Sciences, has been working with colleagues to study the genes that are believed to play a role in the disease. A recent publication by her team has revealed a way of reducing the toxicity associated with a key ALS protein, slowing loss of neuron function and suggesting a possible target for treatment.
Bonini has performed this work in fruit flies, a model organism that has proven valuable in finding genes and molecular pathways important in several neurological diseases, including Alzheimer’s and Parkinson’s.
“These model systems are very fast and simpler than mammalian models,” Bonini says. “They allow us to focus on conserved pathways, and can be remarkably powerful for giving us insight into pathways involved in disease.”
To learn more about ALS, Bonini and other researchers, including Penn Medicine’s John Trojanowski and Virginia Lee, built off earlier studies that identified two genes that appeared to be important factors in ALS: TDP-43 and ataxin-2. When a cell is under stress, both of these proteins go to structures called stress granules, where the production of many proteins is put “on hold” until the cell is no longer stressed and can restart production of its normal suite of proteins.
The team’s experiments in fruit flies showed that genes that promote stress granule formation also increase the toxicity of TDP-43. Flies that were genetically engineered to express the human version of TDP-43 had accumulation of a key marker of stress granule formation, eIF2-alpha phosphorylation. These flies also couldn’t climb as well as normal flies, and died sooner—symptoms akin to those associated with ALS in humans.
Hypothesizing that something about the presence of stress granules may be contributing to disease, the researchers fed the flies a drug that blocks the eIF2-alpha phosphorylation pathway associated with stress granule formation. Flies that consumed this compound retained more of their climbing ability. The same drug also worked to reduce the risk of death of rat neurons in culture expressing TDP-43, providing an early sign that the results may perhaps translate to mammalian cells.
Going forward, Bonini’s team will further pursue the root of this pathway in ALS by returning to the fruit fly as well as investigating other ways that TDP-43 and ataxin-2 interact. With the “united front” of the fly model, complemented with work in yeast, rats, and human tissue, she hopes to keep making progress in finding therapeutic approaches for the devastating disease.
Originally published on December 19, 2013