Rare Diseases

Study reveals how oxidative stress causes damage in incurable Huntington's disease

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Huntington’s disease, an inherited an fatal neurodegenerative disorder, has no cure, but researchers have found a biochemical pathway that may lead to a therapeutic strategy.

In a new study, Johns Hopkins Medicine researchers identified the mechanism through which oxidative stress specifically damages nerve cells in Huntington’s disease. Human cells regulate oxidative stress in many ways, but the process involving amino cysteine may play a key role.

Because cysteine deficiency and oxidative stress have been linked to other diseases, such as Alzheimer’s, arthritis and cancer, study authors noted their findings could point to therapeutic strategies for many serious conditions.

Huntington’s disease affects 30,000 symptomatic Americans and more than 200,000 are at risk of inheriting the disease, according to the Huntington’s Disease Society of America.

The team’s previous research found that the protein responsible for making cysteine, cystathionine gamma-lyase (CSE), is depleted in Huntington’s disease. Cells deficient in CSE are unable to activate the protein-activating transcription pathway 4 (ATF4), which signals cysteine production.  Cells deficient in cysteine by normal pathways may use alternate pathways for a short time, but the cells become overwhelmed by oxidation and die, according to a news release.

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In their study, researchers observed healthy control brain cells and brain cells derived from mice with Huntington’s disease under low-cysteine conditions. First, they saw that healthy cells increased activity of ATF4, but they couldn’t detect the ATF4 in the cells of mice with Huntington’s disease. However, the effect was unique to cysteine— when researchers tested cells in conditions depleted of other amino acids, ATF4 levels were normal in control and Huntington’s cells.

 “That intrigued us, and we wondered if elevated oxidative stress would affect the response of ATF4 because of cysteine’s role in cellular defense,” study author Dr. Bindhu Paul, Ph.D. of the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience, said in the release.

They observed that cells’ expression of ATF4 was greatly reduced when healthy cells were exposed to a strong oxidizing agent then cut off from their cysteine supply. Conversely, Huntington’s cells regained their ability to create ATF4 and make their own cysteine, after they were given an antioxidant, vitamin C.

“These findings implicate a vicious cycle where low levels of cysteine cause oxidative stress, which leads to decreased cysteine levels, therefore creating more oxidative stress, further slowing cysteine production,” study author Juan Sbodio, Ph.D., of the Johns Hopkins University School of Medicine’s Solomon H. Snyder Department of Neuroscience, said in the release.

Study authors noted that antioxidants have long been known as beneficial to health, but they warned that while antioxidants can mitigate disease symptoms in the lab, more information is needed on the role of cysteine in the body before they can validate their therapeutic value.

Researchers warned against supplementing with cysteine to self-medicate.