Peripheral nerve pathology in Niemann-Pick type C mouse

Abstract

The sciatic nerve of the mouse mutant with Niemann-Pick type C disease (NPC mouse) was investigated using light and electron microscopy, and teased-fiber preparations. As early as postnatal day 20, when clinical symptoms were not yet apparent, focal paranodal swellings with an accumulation of small myelin figures in the Schwann cell cytoplasm were noted. These paranodal changes were more pronounced in the distal segment and became progressively conspicuous with increasing age. The morphometric analysis revealed a hypomyelination of large myelinated fibers in the NPC nerves at 70 days, whereas an essentially similar histogram pattern was noted in both control and NPC nerves at 20 days, suggesting progressively defective utilization of cholesterol in the NPC nerves with age. Intraxonal accumulation of dense bodies was noted in older mice, but no segmental demyelination or Wallerian type of axonal degeneration was observed at any age. The changes noted in the paranodal regions in the NPC mouse closely resemble those found in rats treated with an inhibitor of cholesterol biosynthesis, as well as those seen in remodeling fibers during an early stage of peripheral nerve development. Thus, the morphological changes seen in the sciatic nerve of the NPC mouse may be an expression of perturbation in myelin maintenance as a result of defective cholesterol metabolism.