Reversal of defective lysosomal transport in NPC disease ameliorates liver dysfunction and neurodegeneration in the npc1⁻/⁻ mouse

• Published in: Proceedings of the National Academy of Sciences - PNAS 2009-02, Vol.106 (7), p.2377-2382
• Main Authors: Liu, Benny, Turley, Stephen D, Burns, Dennis K, Miller, Anna M, Repa, Joyce J, Dietschy, John M
• Format: Article
• Language: English
• Subjects: 2-Hydroxypropyl-beta-cyclodextrin; Animals; beta-Cyclodextrins - pharmacology; Biological Sciences; Cholesterols; Endocytosis; Female; Liver; Liver - metabolism; Liver - pathology; Liver Diseases - metabolism; Lysosomes - metabolism; Male; Messenger RNA; Mice; Mice, Inbred BALB C; Mice, Transgenic; Nervous system diseases; Neurodegenerative diseases; Neurodegenerative Diseases - metabolism; Niemann Pick diseases; Niemann-Pick Diseases - genetics; Niemann-Pick Diseases - metabolism; Proteins - genetics; Proteins - metabolism; Purkinje cells; Sterols; Tissue Distribution; Type C Niemann Pick disease
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0810895106

Niemann-Pick type C disease is largely attributable to an inactivating mutation of NPC1 protein, which normally aids movement of unesterified cholesterol (C) from the endosomal/lysosomal (E/L) compartment to the cytosolic compartment of cells throughout the body. This defect results in activation of macrophages in many tissues, progressive liver disease, and neurodegeneration. In the npc1⁻/⁻ mouse, a model of this disease, the whole-animal C pool expands from 2,082 to 4,925 mg/kg body weight (bw) and the hepatic C pool increases from 132 to 1,485 mg/kg bw between birth and 49 days of age. A single dose of 2-hydroxypropyl-β-cyclodextrin (CYCLO) administered at 7 days of age immediately caused this sequestered C to flow from the lysosomes to the cytosolic pool in many organs, resulting in a marked increase in cholesteryl esters, suppression of C but not fatty acid synthesis, down-regulation of genes controlled by sterol regulatory element 2, and up-regulation of many liver X receptor target genes. There was also decreased expression of proinflammatory proteins in the liver and brain. In the liver, where the rate of C sequestration equaled 79 mg·d⁻¹·kg⁻¹, treatment with CYCLO within 24 h increased C movement out of the E/L compartment from near 0 to 233 mg·d⁻¹·kg⁻¹. By 49 days of age, this single injection of CYCLO resulted in a reduction in whole-body C burden of >900 mg/kg, marked improvement in liver function tests, much less neurodegeneration, and, ultimately, significant prolongation of life. These findings suggest that CYCLO acutely reverses the lysosomal transport defect seen in NPC disease.