Neurodegeneration in Niemann-Pick type C disease mice

Abstract

Niemann-Pick disease type C (NP-C) is an inherited neurodegenerative disorder associated with intracellular cholesterol and glycolipid trafficking defects. Two separate genes, NPC1 and NPC2, have been linked to NP-C. NPC1 encodes a polytopic membrane-bound protein with a putative sterol-sensing domain. NPC2 has been recently identified as epididymal secretory glycoprotein 1. The NPC1 protein functions in the vesicular redistribution of endocytosed lysosomal cargo, but how its inactivation leads to neurodegeneration is not known. The neurological symptoms of NP-C typically appear after a period of normal early development and reflect progressive degeneration of widespread brain regions. Here we have delineated the pattern of neurodegeneration in NP-C mice, whose genetic defect has been shown to be an inactivating mutation of the mouse NPC1 gene. The results reveal a spatially and temporally specific pattern of degeneration of nerve fibers followed by degeneration of neuronal cell bodies beginning as early as day 9 and continuing throughout life. We have recently showed that in the primate brain, the NPC1 protein is localized predominantly within perisynaptic astrocytic processes. The present observations suggest that a functional disturbance in NPC1 could disrupt vesicular transport of cholesterol, glycolipids and possibly other endocytic cargo in glia, which is critical for maintaining the integrity of neurons.

Neurosteroid regulation of central nervous system development

“…About 95% of human NP-C is caused by mutations in the NPC1 gene (Carstea et al, 1997), and 5% is caused by mutation in the NPC2 gene (Naureckiene et al, 2000). The naturally occurring mutant NP-C mouse (Morris et al, 1982) shows neuronal accumulation of cholesterol and gangliosides (Zervas et al, 2001), cerebellar degeneration (Morris et al, 1982), Purkinje cell degeneration (Higashi et al, 1993), irregular and diminished dendritic spines (Higashi et al, 1993), dysmyelination (Weintraub et al, 1987) and progressive loss of glia, neurons, and myelin (Ong et al, 2001). NP-C mice are hypoandrogenic and have undeveloped reproductive organs (Roff et al, 1993), suggesting a defect in the production of androgens from cholesterol.…”

Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking

“…Many other abnormalities have been reported in very young NPC1 mice. Starting at PND 9, mild abnormalities occur in the corpus callosum, cerebellar white matter, and nerve fibers (52). Also, neuronal cholesterol accumulation occurs in various regions of the brain (53) (Fig.…”

Distribution and Severity of Neuropathology in β-Mannosidase-Deficient Mice is Strain Dependent

“…Following removal from the skull, brains were placed in 4% paraformaldehyde for 24 h, and then transferred to cacodylate storage buffer. Brains were embedded in a 5Â5 array in a gelatin matrix using MultiBrain Technology (NeuroScience Associates, Knoxville, TN) as reported in previous studies (Fix et al 1996;Ong et al 2001). The block of embedded brains was frozen and sectioned coronally at 30 mm beginning at the olfactory bulb and proceeding to the medulla.…”

“…The block of embedded brains was frozen and sectioned coronally at 30 mm beginning at the olfactory bulb and proceeding to the medulla. A serial set of every sixth section was selected for staining with hematoxylin and eosin (H&E), with Weil myelin stain, and with amino cupric silver stain to reveal disintegrative degeneration (Ong et al 2001). A few selected sections were subjected to Nissl staining, GFAP staining for astrocytes, or Iba1 staining for microglia.…”