Ryan Lim and Leslie Thompson
Findings from a study led by UCI’s Ryan Lim and Leslie Thompson validate that the mutation that causes HD leads to impairments in the cell maturation process of the myelin-producing cells that are critical for neuronal health and function, and help clarify how high doses of thiamine and biotin are an effective therapeutic approach. Ryan Lim / UCI and Steve Zylius / UCI

Irvine, Calif., Dec. 21, 2022 — A research team led by the University of California, Irvine has linked the mutation that causes Huntington’s disease to developmental deficits in the brain’s oligodendrocyte cells that are caused by changes in metabolism. They found that high doses of thiamine and biotin can restore normal processes.

OL cells generate the insulating coating around neurons, called myelin. The study, published online in the journal Nature Communications, provides detailed insight into the entire process of how these changes in the genes that regulate cell metabolism impair development of OLs, as well as the therapeutic value of treating HD with high doses of thiamine and biotin. Thiamine and biotin are both B vitamins and are involved in a wide range of metabolic processes that help keep the nervous system healthy.

“Our findings validate that the mutation that causes HD leads to maturation deficits in the myelin-producing cells and show that high-dose thiamine and biotin treatment restores normal function of those cells,” said Leslie Thompson, Ph.D., co-corresponding author and Donald Bren and Chancellor’s professor in the departments of psychiatry & human behavior and biological chemistry at the UCI School of Medicine, and neurobiology & behavior in the School of Biological Sciences.

Using advanced modeling methods, researchers confirmed that in mouse and human HD brain tissue, the maturation state of OL cells and their precursors are arrested in intermediate development, impairing production of the myelin that is critical for neuronal health and function. They found that high doses of thiamine and biotin were connected to significant rescue of gene expression changes in OL cells.

“The mechanisms of HD OL pathology and how these changes occur haven’t been fully understood,” said Ryan Lim, Ph.D., study co-first author and MIND Research Unit project scientist. “Our next steps will be to longitudinally track the effects of thiamine and biotin treatment on HD mice, so that we can further clarify those molecular and cellular processes, assess the efficacy of this therapeutic approach and identify other targets that may benefit HD patients.”

Team members also included co-corresponding author Dr. James E. Goldman, professor of pathology & cell biology, Columbia University College of Physicians & Surgeons; and co-first authors Jie Wu, project scientist at the UCI School of Medicine; and Osama Al Dalahmah, assistant professor of pathology& cell biology, Columbia University College of Physicians & Surgeons; as well faculty and graduate students from the Massachusetts Institute of Technology; and the City University of New York.

This work was funded, in part, by the National Institutes of Health under award numbers R35 NS116872, P01 NS092525 and R01 NS08907.

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