The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells

Kunkel, Thaddeus J.; Townsend, Alice; Sullivan, Kyle A.; Merlet, Jean; Schuchman, Edward H.; Jacobson, Daniel A.; Lieberman, Andrew P.

doi:10.1038/s41467-023-39733-6

Title: The cholesterol transporter NPC1 is essential for epigenetic regulation and maturation of oligodendrocyte lineage cells

Journal Article · Wed Jul 05 00:00:00 EDT 2023 · Nature Communications

DOI:https://doi.org/10.1038/s41467-023-39733-6· OSTI ID:1989570

Kunkel, Thaddeus J. ^[1]; Townsend, Alice ^[2];

^[3]; Merlet, Jean ^[4]; Schuchman, Edward H. ^[5];

^[3];

^[1]

Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Tennessee, Knoxville, TN (United States); Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). Computational and Predictive Biology
Univ. of Tennessee, Knoxville, TN (United States)
Icahn School of Medicine at Mount Sinai, New York, NY (United States)

The intracellular cholesterol transporter NPC1 functions in late endosomes and lysosomes to efflux unesterified cholesterol, and its deficiency causes Niemann–Pick disease Type C, an autosomal recessive lysosomal disorder characterized by progressive neurodegeneration and early death. Here, we use single-nucleus RNA-seq on the forebrain of Npc1^–/– mice at P16 to identify cell types and pathways affected early in pathogenesis. Our analysis uncovers significant transcriptional changes in the oligodendrocyte lineage during developmental myelination, accompanied by diminished maturation of myelinating oligodendrocytes. We identify upregulation of genes associated with neurogenesis and synapse formation in Npc1^–/– oligodendrocyte lineage cells, reflecting diminished gene silencing by H3K27me3. Npc1^–/– oligodendrocyte progenitor cells reproduce impaired maturation in vitro, and this phenotype is rescued by treatment with GSK-J4, a small molecule inhibitor of H3K27 demethylases. Moreover, mobilizing stored cholesterol in Npc1^–/– mice by a single administration of 2-hydroxypropyl-β-cyclodextrin at P7 rescues myelination, epigenetic marks, and oligodendrocyte gene expression. Our findings highlight an important role for NPC1 in oligodendrocyte lineage maturation and epigenetic regulation, and identify potential targets for therapeutic intervention.

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Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE; National Institutes of Health (NIH)

Grant/Contract Number:: AC05-00OR22725; R01 NS122746; T32 GM113900; R01 DA051913; R01 DA051908

OSTI ID:: 1989570

Journal Information:: Nature Communications, Vol. 14, Issue 1; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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