Temporal and cell-specific deletion establishes that neuronal Npc1 deficiency is sufficient to mediate neurodegeneration

Ting Yu, Vikram G. Shakkottai, Chan Chung, Andrew P. Lieberman

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Niemann-Pick type C (NPC) disease is an autosomal recessive lysosomal storage disorder caused by mutations in the NPC1 or NPC2 genes. Loss of function mutations in either gene disrupt intracellular lipid trafficking and lead to a clinically heterogeneous phenotype that invariably includes neurological dysfunction and early death. The mechanism by which impaired lipid transport leads to neurodegeneration is poorly understood. Here we used mice with a conditional null allele to establish the timing and cell type that underlie neurodegeneration due to Npc1 deficiency. We show that global deletion of Npc1 in adult mice leads to progressive weight loss, impaired motor function and early death in a time course similar to that resulting from germline deletion. These phenotypes are associated with the occurrence of characteristic neuropathology including patterned Purkinje cell loss, axonal spheroids and reactive gliosis, demonstrating that there is not a significant developmental component to NPC neurodegeneration. Furthermore, we show that these same changes occur when Npc1 is specifically deleted only in neurons, establishing that neuronal deficiency is sufficient to mediate central nervous system (CNS) disease. In contrast, astrocyte-specific deletion does not impact behavioral phenotypes, CNS histopathology or synaptic function. We conclude that defects arising in neurons, but not in astrocytes, are the determining factor in the development of NPC neuropathology.

Original languageEnglish (US)
Article numberddr372
Pages (from-to)4440-4451
Number of pages12
JournalHuman molecular genetics
Issue number22
StatePublished - Nov 2011
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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