PERK-ATF4 Pathway Holds Promise for Oxidative Stress Protection in Huntington Disease


Exposure to monesin has been shown to combat stress by oxidants and free radicals via the protein kinase R-like endoplasmic reticulum kinase/activating transcription factor 4 pathway.

Bindu D. Paul, PhD, MS

A recently discovered biochemical pathway, the protein kinase R-like endoplasmic reticulum kinase/activating transcription factor 4 (PERK-ATF4) pathway, has been shown to be a feasible route to develop protective methods for oxidative stress, commonly associated with Huntington disease (HD).

In 2014, previous work led by Bindu D. Paul, PhD, MS, an instructor of neuroscience at the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience, identified that majorly depleting cystathionine γ-lyase (CSE), a biosynthetic enzyme for cysteine in HD tissue, held promise for mediating HD pathophysiology.1 Although, a possible consequence of depriving cells of cysteine is an increase in oxidative stress—in turn increasing the rapid production of glutathione to combat the stress.

Now, using similar thinking, Paul and a team of colleagues has found that taking advantage of the reactive processes of this new pathway, which impacts the protein-transporting Golgi apparatus. The cell structure, when exposed to an ionophore, monensin, combats oxidants and free radicals through its stress response via the PERK/ATF4 pathway.2

“We haven’t done anything in patients, but this is very promising,” Paul told Rare Disease Report, a sister publication of NeurologyLive. “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 order to better understand the use of monensin in this process, Paul and colleagues exposed cells to low doses of the antibiotic, noting that enhancing “ATF4 by monensin is concentration-dependent with a modest augmentation evident at 0.1 μM monensin and increased stimulation at concentrations from 5 to 10 μM. CSE is also induced in response to monensin treatment.”

After treatment, PERK, ATF4, and CSE all 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 I. Sbodio, PhD, a 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.”

Paul and Sbodio’s previous work in CSE depletion pushed them to seek to identify how to increase cells impacted by oxidative stress or free radicals using cysteine production. So, they took lab-grown cells with mimicked HD, depleted their cysteine, and exposed some of them to a small dose of monensin. Those treated grew in standard fashion for the 7- to 9-day experiment period, while those that went untreated died.

Noting that as the cell death normally elicited by cysteine starvation in cell lines disrupted by HD is prevented by monensin exposure, Paul and colleagues wrote that “these findings support the notion that enhancement of the reverse transsulfuration pathway as a whole may be therapeutic in HD.”

Paul and her team believe 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,” Paul said. “Now, we have found this new biochemical signaling pathway that can offer protection.”

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


1. Paul BD, Sbodio JI, Xu R, et. al. Cystathionine γ-lyase deficiency mediates neurodegeneration in Huntington’s disease. Nature. 2014;509(7498):96-100.


: 10.1038/nature13136.

2. Sbodio JI, Snyder SH, Paul BD. Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington’s disease. P Natl Acad Sci USA. 2018;20(171):78-77.


: 10.1073/pnas.1717877115.

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