Summary: Researchers report that oligodendrocytes in the brain differ fundamentally from those in the spinal cord because of distinct metabolic programs. These discoveries could improve understanding of myelin loss in multiple sclerosis and other neurodegenerative or neurodevelopmental conditions and guide new therapeutic strategies.
Source: Rutgers
New research offers a clearer path to identifying immature cells in the central nervous system that can form myelin, the insulating substance essential for nerve function. This work may help explain mechanisms behind neurodegenerative diseases such as multiple sclerosis and support development of more effective therapies.
Published in the journal Cell Reports, the Rutgers study focused on oligodendrocytes—the cells in the brain and spinal cord responsible for producing myelin. Myelin coats axons, enabling rapid electrical signaling and protecting neural circuits.
Using molecular and biochemical analyses, the research team found that oligodendrocytes in the brain differ substantially from those in the spinal cord: their metabolic programs, especially how they synthesize cholesterol, are distinct. Cholesterol is a critical component of myelin, and differences in its production may influence where and how myelin is made or repaired.
“Under the microscope these cells look very similar, so it was assumed they function the same. By examining their biochemistry and gene activity, we discovered clear and meaningful differences,” said Teresa Wood, Distinguished Professor and Rena Warshow Endowed Chair in Multiple Sclerosis at Rutgers New Jersey Medical School, who led the study.
Identifying metabolic distinctions between brain and spinal cord oligodendrocytes could help scientists target specific cell populations to enhance myelin formation or protect existing myelin. That precision may be especially important in conditions characterized by focal myelin loss.
In multiple sclerosis, brain and spinal cord imaging often reveals lesions where myelin has been lost and oligodendrocytes have died. Myelin loss can cause symptoms ranging from visual impairment to motor dysfunction. Similar myelin abnormalities are observed in imaging studies of Alzheimer’s disease, autism and schizophrenia, although the causal relationships remain unclear.
A major therapeutic goal is to locate and stimulate immature precursor cells distributed throughout the central nervous system so they can mature into myelin-producing oligodendrocytes and repair damaged regions. Detailed knowledge of oligodendrocyte biology—including regional metabolic differences—is essential to designing treatments that promote myelin repair where it is needed most.
“Understanding the mechanisms that regulate myelin production and maintenance is key to better therapies for neurodegenerative diseases and for recovery after injury,” Wood added. She is also a member of the Cancer Metabolism and Growth Program at Rutgers Cancer Institute of New Jersey.
The study produced three principal findings that clarify how oligodendrocytes differ between brain and spinal cord:
- Cholesterol production: Spinal cord oligodendrocytes synthesize cholesterol more efficiently and at higher levels than brain oligodendrocytes. Because cholesterol is a foundational component of myelin, these regional differences in biosynthesis could influence vulnerability to myelin loss and the capacity for repair.
- Role of mTOR in biosynthesis: The protein mTOR (mechanistic target of rapamycin) is required for normal cholesterol production in oligodendrocytes. Targeting mTOR-regulated pathways may offer a route to enhance cholesterol and myelin synthesis when beneficial.
- mTOR and myelin maintenance: Beyond development, mTOR activity is important for preserving existing myelin structures in the adult central nervous system, indicating that metabolic regulation affects both formation and long-term stability of myelin.
Graduate researchers Luipa Khandker and Marisa Jeffries—who completed doctoral degrees following this work—served as lead and major contributing authors, respectively.
About this neurology research news
Author: Press Office
Source: Rutgers
Contact: Press Office – Rutgers
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Original Research: Open access. “Cholesterol biosynthesis defines oligodendrocyte precursor heterogeneity between brain and spinal cord” by Luipa Khandker et al., Cell Reports.
Abstract
Cholesterol biosynthesis defines oligodendrocyte precursor heterogeneity between brain and spinal cord
Highlights
- Single-cell RNA sequencing reveals distinct oligodendrocyte precursor populations in the brain versus the spinal cord.
- Brain and spinal cord oligodendroglia differentially regulate cholesterol synthesis, defining regional metabolic specializations.
- mTOR is necessary for normal cholesterol biosynthesis in oligodendroglia during development.
- mTOR signaling also supports long-term myelin maintenance in the adult central nervous system.
Summary
Oligodendroglia from the brain and spinal cord possess distinct functional profiles, and the loss of specific genes within these cells can produce different regional phenotypes. The molecular basis for these differences centers largely on cholesterol biosynthesis pathways.
Using single-cell analysis during developmental myelination, the authors show that brain and spinal cord oligodendrocyte precursors are transcriptionally distinct, with cholesterol production genes among the most divergent. The mechanistic target of rapamycin (mTOR) emerges as a key regulator that promotes cholesterol biosynthesis in oligodendroglia.
Oligodendroglia-specific deletion of mTOR reduces cholesterol biosynthesis in both regions but has a greater developmental impact in the spinal cord, reflecting larger deficits in myelination. In the brain, loss of mTOR leads to progressive adult myelin deficits, including oligodendrocyte loss, spontaneous demyelination and impaired axonal function, demonstrating that mTOR is essential for maintaining myelin integrity in the adult brain.