Npc1 acting in neurons and glia is essential for the formation and maintenance of CNS myelin

PLoS Genet. 2013 Apr;9(4):e1003462. doi: 10.1371/journal.pgen.1003462. Epub 2013 Apr 11.


Cholesterol availability is rate-limiting for myelination, and prior studies have established the importance of cholesterol synthesis by oligodendrocytes for normal CNS myelination. However, the contribution of cholesterol uptake through the endocytic pathway has not been fully explored. To address this question, we used mice with a conditional null allele of the Npc1 gene, which encodes a transmembrane protein critical for mobilizing cholesterol from the endolysosomal system. Loss of function mutations in the human NPC1 gene cause Niemann-Pick type C disease, a childhood-onset neurodegenerative disorder in which intracellular lipid accumulation, abnormally swollen axons, and neuron loss underlie the occurrence of early death. Both NPC patients and Npc1 null mice exhibit myelin defects indicative of dysmyelination, although the mechanisms underlying this defect are incompletely understood. Here we use temporal and cell-type-specific gene deletion in order to define effects on CNS myelination. Our results unexpectedly show that deletion of Npc1 in neurons alone leads to an arrest of oligodendrocyte maturation and to subsequent failure of myelin formation. This defect is associated with decreased activation of Fyn kinase, an integrator of axon-glial signals that normally promotes myelination. Furthermore, we show that deletion of Npc1 in oligodendrocytes results in delayed myelination at early postnatal days. Aged, oligodendocyte-specific null mutants also exhibit late stage loss of myelin proteins, followed by secondary Purkinje neuron degeneration. These data demonstrate that lipid uptake and intracellular transport by neurons and oligodendrocytes through an Npc1-dependent pathway is required for both the formation and maintenance of CNS myelin.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Central Nervous System / metabolism*
  • Central Nervous System / pathology
  • Cholesterol* / metabolism
  • Endocytosis
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Mice
  • Myelin Sheath / metabolism*
  • Neuroglia / metabolism
  • Neuroglia / pathology
  • Neurons / metabolism
  • Neurons / pathology
  • Niemann-Pick Disease, Type C* / genetics
  • Niemann-Pick Disease, Type C* / metabolism
  • Niemann-Pick Disease, Type C* / pathology
  • Oligodendroglia / cytology
  • Oligodendroglia / metabolism
  • Proteins* / genetics
  • Proteins* / metabolism
  • Proto-Oncogene Proteins c-fyn / metabolism
  • Purkinje Cells / cytology
  • Purkinje Cells / metabolism


  • Intracellular Signaling Peptides and Proteins
  • Npc1 protein, mouse
  • Proteins
  • Cholesterol
  • Proto-Oncogene Proteins c-fyn