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

Summary: Lipids responsible for neural function are highly active and not inert. The findings challenge traditional beliefs about mature myelin.

Source: M.D Anderson Cancer Center

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.

This shows a brain
Diseases such as multiple sclerosis occur when myelin is damaged, a process known as demyelination. The image is in the public domain.

“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.

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.

Funding: 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.

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Source:
M.D Anderson Cancer Center
Media Contacts:
Ron Gilmore – M.D Anderson Cancer Center
Image Source:
The image is in the public domain.

Original Research: Open access
“Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα–mediated lipid metabolism”. Xin Zhou, Chenxi He, Jiangong Ren, Congxin Dai, Sharon R. Stevens, Qianghu Wang, Daniel Zamler, Takashi Shingu, Liang Yuan, Chythra R. Chandregowda, Yunfei Wang, Visweswaran Ravikumar, Arvind U.K. Rao, Feng Zhou, Hongwu Zheng, Matthew N. Rasband, Yiwen Chen, Fei Lan, Amy B. Heimberger, Benjamin M. Segal, Jian Hu.
Journal of Clinical Investigation doi:10.1172/JCI131800.

Abstract

Mature myelin maintenance requires Qki to coactivate PPARβ-RXRα–mediated lipid metabolism

Lipid-rich myelin forms electrically insulating, axon-wrapping multilayers that are essential for neural function, and mature myelin is traditionally considered metabolically inert. Surprisingly, we discovered that mature myelin lipids undergo rapid turnover, and quaking (Qki) is a major regulator of myelin lipid homeostasis. Oligodendrocyte-specific Qki depletion, without affecting oligodendrocyte survival, resulted in rapid demyelination, within 1 week, and gradually neurological deficits in adult mice. Myelin lipids, especially the monounsaturated fatty acids and very-long-chain fatty acids, were dramatically reduced by Qki depletion, whereas the major myelin proteins remained intact, and the demyelinating phenotypes of Qki-depleted mice were alleviated by a high-fat diet. Mechanistically, Qki serves as a coactivator of the PPARβ-RXRα complex, which controls the transcription of lipid-metabolism genes, particularly those involved in fatty acid desaturation and elongation. Treatment of Qki-depleted mice with PPARβ/RXR agonists significantly alleviated neurological disability and extended survival durations. Furthermore, a subset of lesions from patients with primary progressive multiple sclerosis were characterized by preferential reductions in myelin lipid contents, activities of various lipid metabolism pathways, and expression level of QKI-5 in human oligodendrocytes. Together, our results demonstrate that continuous lipid synthesis is indispensable for mature myelin maintenance and highlight an underappreciated role of lipid metabolism in demyelinating diseases.

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