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Role of LXRβ in oligodendrocytes in neuronal survival

Molecular Psychiatry (2025)Cite this article

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Abstract

We have reported that mice in which the liver X receptor β (LXRβ) gene is inactivated lose dopaminergic neurons in the substantia nigra and motor neurons in the ventral horn of the spinal cord. These mice develop progressive hind limb paralysis starting at 6 months of age. Since LXRβ is not expressed in either dopaminergic neurons or motor neurons, we have focused on LXRβ-expressing cells whose function is essential for neuron survival. We now report defects in oligodendrocyte maturation in the absence of LXRβ. At 4 months of age, long before motor neuron loss occurs, there was reduction in expression of the four following genes in oligodendrocytes: The monocarboxylate transporter 1 (MCT1), which is essential for metabolic support of motor neurons; BDNF, a motor neuron trophic factor; 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), a rate-limiting enzyme in cholesterol synthesis; glutamine synthetase (GS), an enzyme crucial for the elimination of neurotoxic glutamate from synapses. Differentiation of ES cells from WT and LXRβ−/− mice into motor neurons/oligodendrocytes revealed that LXRβ−/− cultures showed less arborization of motor neurons and a reduced proportion of mature oligodendrocytes. Our study suggests that defects in glial cells can have profound effects on neuronal survival and that early defective oligodendrocyte maturation can lead to motor neuron death. The expression of LXRβ in oligodendrocytes should be investigated as a target for preventing neuronal loss in diseases such as amyotrophic lateral sclerosis (ALS) and Parkinson’s disease.

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Fig. 1: Loss of LXRβ leads to the loss of neuronal dendrites and motor neuron degeneration in the spinal cord.
Fig. 2: Differentiation of MNPs into mixed motor neurons and oligodendrocytes.
Fig. 3: Decreased MCT1 expression in oligodendrocytes in the spinal cord of LXRβ−/− mice.
Fig. 4: Decreased BDNF expression in oligodendrocytes in the spinal cord of LXRβ−/− mice.
Fig. 5: Decreased HMGCR expression in oligodendrocytes in the spinal cord of LXRβ−/− mice.
Fig. 6: Decreased GS expression in oligodendrocytes in the spinal cord of LXRβ−/− mice.
Fig. 7: No significant difference in the number of total oligodendrocytes in the spinal cord of LXRβ−/− mice.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary files. The datasets of the current study are available from the corresponding author on reasonable request.

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Acknowledgements

J.-Å. G. acknowledges Robert A. Welch Foundation grant E-0004 and the Swedish Research Council.

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Authors and Affiliations

  1. Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, 77204, USA

    Xiaoyu Song, Wanfu Wu, Andrew Roman, Jan-Åke Gustafsson & Margaret Warner

  2. Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden

    Mukesh Varshney

  3. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden

    Jan-Åke Gustafsson

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  1. Xiaoyu Song
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Contributions

XS, MW, and JAG designed the research, analyzed the data, and wrote the manuscript. XS, WW, MV, AR, and MW performed the research. All authors read and approved the final version of the manuscript.

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Correspondence to Xiaoyu Song or Jan-Åke Gustafsson.

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All methods in this study were performed in accordance with the relevant guidelines and regulations. Ethical approval for this study was obtained from the local Animal Experimentation Ethics Committee for animal experimentation (University of Houston animal protocol 09-036). All participants provided written informed consent before participation.

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Song, X., Wu, W., Varshney, M. et al. Role of LXRβ in oligodendrocytes in neuronal survival. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03278-5

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