Rare Disease Report

New Pathway Identified in Huntington's Disease Cells

MARCH 09, 2018
Mathew Shanley
A newly-discovered biochemical pathway could assist scientists develop new ways to protect cells against the oxidative stress that is commonly associated with Huntington’s disease (HD).

A team of researchers, led by Bindu Paul, M.S., Ph.D., instructor of neuroscience at the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience, believe that the pathway allows a structure within cells – referred to as the Golgi apparatus – to combat stress caused by free radicals and oxidants.

“We haven’t done anything in patients, but this is very promising,” said Paul in an exclusive interview with Rare Disease Report. “Specifically, what we’ve done is discover a way that we can enhance a pathway, and uphold the protection of the cells with a method similar to vaccination.”

In 2014, a study conducted by Paul and published in Nature, suggested that a major depletion of cystathionine γ-lyase (CSE), the biosynthetic enzyme for cysteine in Huntington’s disease tissues, could potentially mediate the pathophysiology of HD.

When a cell is exposed to cysteine deprivation, though, it can potentially increase oxidative stress, resulting in the cell producing more glutathione at a rapid rate. Glutathione binds to and neutralizes oxidating agents, combating oxidative stress. The Golgi, which is best known for its ability to transport proteins to their proper locations, employs a similar process to induce stress when it is exposed to the antibiotic monensin, which is commonly used in animal feed.

To gain a better understanding for monensin and its effects, Paul and her team bathed cells in low doses of it; high doses of the drug are known to dismember the Golgi. It was concluded after treatment that the proteins PERK, ATF4 and CSE appeared in elevated levels within the cell compared to nontreated cells.

“We wanted to find a way to make up for the lack of enzymes responsible for cysteine,” said Juan Sbodio, Ph.D., postdoctoral fellow at Johns Hopkins University School of Medicine's Solomon H. Snyder Department of Neuroscience. 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.”

Because of the previous research conducted by Paul in 2014, her team believe that neurons with HD are incapable of counteracting dangerous free radicals or oxidants and are at risk of dying from stress. In an attempt to discover a way to increase afflicted cells by increasing cysteine production, lab-grown mouse cells that mimicked human HD were given a small dose of monensin and depleted cysteine in their nutrient bath.

The cells treated with the drug grew typically for 7-9 days during the experiment, compared to those that were not treated which withered away.

It is the belief of Paul and her team that the treatment built up the cell’s reserve of CSE and cysteine, protecting the cells against low cysteine levels. It was also suggested that this stress response pathway triggers another pathway responsible for creating hydrogen sulfide.

“Golgi stress response has never been well-categorized,” said Paul. “Now, we have found this new biochemical signaling pathway that can offer protection.”

The team at Johns Hopskins hopes to further study the pathway’s role in overall cellular health.

Further details of the pathway, which involves the response from a series of proteins, are reported in the January 9 issue of the Proceedings of the National Academy of Sciences.

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