Journal
JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY
Volume 64, Issue 4, Pages 323-333Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1093/jnen/64.4.323
Keywords
apolipoprotein B-100; apolipoprotein E; LDLR related protein; low-density lipoprotein receptor; LXR nuclear receptor; purkinje cells; neurodegeneration
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Funding
- NHLBI NIH HHS [R 37 HL09610] Funding Source: Medline
- NIGMS NIH HHS [GM07062] Funding Source: Medline
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In Niemann-Pick type C (NPC) disease, cholesterol associated with either apoE or apoB(100) is taken up by cells in all tissues, including the central nervous system, through clathrin-coated pits and becomes trapped in late endosomes and lysosomes. This study defines the functional, biochemical, and molecular events that ensue as nerve cell death occurs. In mice homozygous for a mutation in NPC1, neuromuscular dysfunction begins at 5 weeks and death occurs at 13 weeks of age. Cholesterol accumulates in every tissue in the body. Purkinje cell loss in the cerebellum begins at 3 to 4 weeks of age and is nearly complete by 11 weeks. This neurodegeneration in the cerebellum is associated with increases in the levels of mRNA for caspase 1, caspase 3, NPC2, LipA, apoE, apoD, glial fibrillary acidic protein, and tumor necrosis factor-alpha, but not for most target genes of the LXR nuclear receptors. The level for apoER2 is significantly reduced. These studies show there is a compensatory increase in NPC2 and LipA in an attempt to overcome the physiological defect caused by the mutation. Nevertheless, neurodegeneration proceeds utilizing apoptosis with activation of glial cells, increased apoE and apoD synthesis, and increased cholesterol turnover across the CNS.
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