Antibiotic May Protect Huntington’s Nerve Cells from Death, Mouse Study Suggests
Monensin, an antibiotic widely used in feed for animals like cows that chew their cud, can help protect cells against oxidative stress linked to Huntington’s disease, according to a new mouse study.
The biochemical pathway that allows a cellular structure known as the Golgi apparatus to fight this oxidative stress was also identified by Johns Hopkins researchers.
The study, “Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington’s disease,” was published in the journal Proceedings of the National Academy of Sciences.
The Golgi is like a central station where proteins arrive to be modified before shuttling to different parts of the cell. This small cellular organelle acts as a sensor of cellular stress by increasing the production of the aminoacid cysteine — one of the building blocks of proteins.
Cysteine is vital for the body’s natural antioxidant responses, including the production of an antioxidant molecule called glutathione.
When exposed to cysteine deprivation and oxidative stress, cells send alarm signals to produce more cysteine and, consequently, create glutathione.
“Normally, elevated oxidative stress is not good for cells, as it can compromise their natural protective responses,” Bindu Paul, PhD, instructor of neuroscience at the Johns Hopkins University School of Medicine and the study’s lead author, said in a press release.
In Huntington’s disease, an enzyme that aids the production of cysteine, called cystathionine γ-lyase (CSE), is severely depleted. As a result, Huntington’s nerve cells are more sensitive to the damaging effects of oxidative stress and more prone to die from it.
To discover whether other forms of stress can also be influenced by CSE levels, researchers tested the effects of the monensin — a Golgi stress inducer which is commonly used as an antibiotic in animal feed.
Mouse cells incubated with low doses of monensin had increased CSE levels, which occurred through the activation of two proteins: PERK and ATF4.
Of note, the induction of ATF4 is compromised in Huntington’s neuronal cell lines in response to low-cysteine conditions.
To understand if there was a way to increase cysteine production in compromised cells to protect them, two different mouse nerve cell lines mimicking Huntington’s were again treated with a small dose of monensin, and this time cysteine was depleted from the cells’ nutrient bath.
The cells treated with the antibiotic grew normally for seven to nine days, while those that werent’ treated with monensin died.
“We think that the monensin treatment built up the cell’s reserve of CSE and cysteine, protecting the cells against low cysteine levels,” Paul said.
Treatment with monensin also increased the production of CSE-mediated hydrogen sulphide, an antioxidant in the form of gas that protects, among other things, endothelial cells in blood vessels against oxidative stress.
“We showed that we can enhance a pathway that protects the cells with a method that resembles vaccination. By giving a lower, less potent, dose of the stressor, you can boost the cell’s response so that it has a robust reaction to the real threat later on,” said the study’s first author, Juan Sbodio, PhD.
“Low-grade Golgi stress induced by monensin preconditions cells to tolerate cysteine deficiency associated with Huntington’s disease. These findings are relevant to not only [Huntington’s], but also other diseases involving redox imbalance,” researchers wrote.
“Targeting the molecular controls for restoration of cysteine balance may offer more robust therapeutic avenues for disease management,” they added.