Study sheds light on fatty acid's role in 'chemobrain' and multiple sclerosis

March 23, 2020

HOUSTON -- Medical experts have always known myelin, the protective coating of nerve cells, to be metabolically inert. A study led by The University of Texas MD Anderson Cancer Center has found that myelin is surprisingly dynamic, a discovery that has implications for treatment of multiple sclerosis and a type of myelin damage caused by some chemotherapy drugs, often referred to as "chemobrain." Chemobrain can occur in up to 70 percent of patients receiving chemotherapy, leaving them with temporary and even permanent thinking and memory impairment.

Study findings were published in the March 23 online issue of the Journal of Clinical Investigation.

Myelin is comprised of fatty substances and proteins, and when wrapped around neural nerves such those found in the brain and spinal cord, allows electrical impulses to transmit quickly and efficiently along the nerve cells. Diseases such as multiple sclerosis occur when myelin is damaged, a process known as demyelination.

"We actually found that mature myelin is often damaged when cancer patients are treated with various types of chemotherapy drugs and is probably the most consistent manifestation of chemotherapy-induced neurotoxicity," said Study Lead, Jian Hu, Ph.D., assistant professor of Cancer Biology. "Our study shows that mature myelin is a very dynamic material, particularly its lipid components, and it disproves a dogma held for decades, if not a century, that mature myelin is a very stable substance."

Hu's team shows that mature myelin lipids undergo rapid turnover and require an RNA-binding protein known as the quaking or Qki to perform normally. Qki depletion resulted in quick demyelination and gradual neurologic deficits when observed in mice.

Significantly, Qki served as a co-activator of the neural signaling proteins called peroxisome proliferator-activated receptors (PPAR), which play a role in controlling transcription of lipid metabolism genes by working with their partners retinoid X receptors (RXRs). Hu's team found that Qki interacts with a PPAR isoform called PPAR-beta and RXR-alpha to modulate this transcription, opening up a potential new approach to treating demyelination.

"Treatment of Qki-depleted mice with drugs like PPAR-beta or RXR-alpha agonists greatly alleviated neurological disability and extended survival durations," said Hu. "Furthermore, a subset of lesions from patient samples with primary progressive multiple sclerosis were characterized by downregulation of key activities in lipid metabolism associated with Qki and PPAR-beta/RXR-alpha."

"Together, the team demonstrated that continuous lipid production is indispensable for mature myelin maintenance and highlights an underappreciated role of lipid metabolism in demyelinating diseases and cancer therapy related adverse effects such as chemobrain", Hu said.
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MD Anderson study team participants included Xin Zhou, Ph.D.; Jiangong Ren, Ph.D.; Congxin Dai, Ph.D.; Takashi Shingu, Ph.D.; Liang Yuan, Ph.D.; and Chythra Chandregowda, all of the Department of Cancer Biology; Daniel Zamler, of the Department of Genomic Medicine; Yunfei Wang, Ph.D., of the Department of Melanoma Medical Oncology; Yiwen Chen, Ph.D., of the Department of Bioinformatics and Computational Biology; and Amy Heimberger, M.D., of the Department of Neurosurgery.

Other participating institutions included Fudan University, Shanghai; Peking Union Medical College, Beijing; Baylor College of Medicine, Houston; Nanjing Medical University, Najing, China; Tufts University, Boston; University of Michigan, Ann Arbor, Mich.; Carcinogenesis and Cancer Invasion, Minister of Education, and Institutes of Biomedical Sciences, Shanghai; Weil Cornell Medicine College, New York; and The Ohio State University, Columbus, Ohio.

The study was funded by the National Institutes of Health (P30CA016672, R37CA214800); the National Multiple Sclerosis Society; the Cancer Prevention and Research Institute of Texas (RP120348 and RP170002); The University of Texas Rising STARS Award; the Sidney Kimmel Scholar Award; the Sontag Foundation Distinguished Scientist Award; and the Brockman Foundation. The investigators reported no disclosures.

About MD Anderson

The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world's most respected centers focused on cancer patient care, research, education and prevention. The institution's sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 51 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No.1 for cancer care in U.S. News & World Report's "Best Hospitals" survey. It has ranked as one of the nation's top two hospitals for cancer care since the survey began in 1990, and has ranked first 15 times in the last 18 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).

University of Texas M. D. Anderson Cancer Center

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