A team headed by researchers at the University of Pennsylvania has figured out a way to reduce the toxicity of Lou Gehrig's disease by slowing neuron dysfunction in animal models. The discovery could offer a new way to treat the disease, also known as amyotrophic lateral sclerosis, or ALS.
Previous studies by the Penn team found that TDP-43, a gene linked with ALS, interacts with a gene called ataxin-2, which on its own is a gene whose mutations cause human degenerative disease.
Using fruit fly models of the disease, investigators found that genes controlling cellular structures known as stress granules, which act as holding pens for RNA and proteins when cells are under stress, also modify TDP-43 toxicity. Previous research has suggested that ALS patients may have abnormal buildups of these stress granule components. The team found that when a set of genes that promote stress granules were expressed, it correlated with an increased in the toxic activity of TDP-43.
To test reversing TDP-43 toxicity, the researchers used a compound developed by GlaxoSmithKline ($GSK) that reduces eIF2α phosphorylation, which is associated with the formation of stress granules. Flies expressing TDP-43 that were fed the compound showed greater physical strength and more climbing ability than those that were not treated with the compound. When tested in rat neuron cells expressing TDP-43, researchers found that the compound reduced the risk of cell death.
Researchers say the findings, which are published in Nature Genetics, could provide the groundwork for new therapies to treat ALS.
ALS is a fatal neurodegenerative disease that gradually degrades motor neurons in the brain, causing the loss of major motor functions, including walking, speaking, swallowing and breathing. The disease is usually fatal within 5 years of diagnosis. There is no cure for ALS and, so far, only one FDA-approved drug, riluzole, which extends the lifespans of patients by an average of only three months.
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