CHOLESTEROL REUTILIZATION DURING MYELINATION OF REGENERATING PNS AXONS IS IMPAIRED IN NIEMANN-PICK DISEASE TYPE-C MICE

Niemann-Pick C (NPC) disease is an autosomal recessive lipidosis chara cterized by lysosomal accumulations of unesterified cholesterol. Cultu red NPC cells exhibit a defect in the intracellular trafficking of LDL -derived cholesterol that leads to lysosomal accumulations of unesteri fied cholesterol. We found in a preliminary study that the myelination of regenerating axons was retarded in the NPC mouse following sciatic nerve crush, Because lipoprotein-mediated cholesterol transport is in volved in myelination during nerve regeneration, we investigated wheth er this cholesterol reutilization pathway was perturbed in the NPC mou se, Mice received intraneural injections of [H-3]acetate to label myel in cholesterol, and 2 weeks later the injected nerves were crushed abo ve the injection site, Four weeks after crush, the nerves were examine d by electron microscopic autoradiography, In normal mice, regeneratio n was well advanced, with thick myelin sheaths surrounding the regener ated axons and very little myelin debris remaining, The new myelin she aths were well labeled, indicative of efficient cholesterol reutilizat ion, In NPC mice, the new myelin sheaths were thinner and contained li ttle label, indicative of retarded regeneration and little or no chole sterol reutilization, These data suggest the possibility of a causal l ink between compromised cholesterol reutilization and delayed or slowe d regeneration of myelin sheaths, (C) 1997 Wiley-Liss, Inc.