Abstract
Niemann-Pick disease type C (NPC) is a lethal neurologic storage disorder of children most often caused by a defect in the protein NPC1. To better understand the disease we thoroughly characterized the cellular and morphological alterations occurring in murine, feline, and human NPC. Using immunocytochemistry and filipin histochemistry we show that both gangliosides and unesterified cholesterol are differentially stored in neurons of the cerebral cortex, cerebellum, and hippocampus, as well as in liver. Double fluorescence labeling revealed that GM2 ganglioside and unesterified cholesterol were partially co-localized in vesicular structures, and triple fluorescence labeling utilizing a LAMP-1 antibody identified many of these organelles as part of the late endosomal/lysosomal pathway. These observations, coupled with the proposed role of NPC1 in intracellular cholesterol movement, suggest that GM3 and GM2 gangliosides as well as unesterified cholesterol may be retrogradely cleared from late endosomes/lysosomes by an NPC1-dependent mechanism. Cellular consequences of the NPC metabolic defect as shown by parvalbumin immunocytochemistry and rapid Golgi staining, respectively, revealed characteristic axonal spheroids on GABAergic neurons and ectopic dendritogenesis that followed a species-specific gradient of: mouse < feline < human. These studies suggest that the homeostatic regulation of gangliosides and cholesterol in neurons is mediated by NPC1 and that perturbations in this mechanism cause a complex neuronal storage disorder.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 49-64 |
| Number of pages | 16 |
| Journal | Journal of Neuropathology and Experimental Neurology |
| Volume | 60 |
| Issue number | 1 |
| State | Published - 2001 |
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Keywords
- Axonal Spheroid
- Dendrite
- Endosome
- Ganglioside
- Lysosome
- Meganeurite
- Unesterified cholesterol
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Neuroscience(all)
Cite this
Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations. / Zervas, Mark; Dobrenis, Kostantin; Walkley, Steven U.
In: Journal of Neuropathology and Experimental Neurology, Vol. 60, No. 1, 2001, p. 49-64.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations
AU - Zervas, Mark
AU - Dobrenis, Kostantin
AU - Walkley, Steven U.
PY - 2001
Y1 - 2001
N2 - Niemann-Pick disease type C (NPC) is a lethal neurologic storage disorder of children most often caused by a defect in the protein NPC1. To better understand the disease we thoroughly characterized the cellular and morphological alterations occurring in murine, feline, and human NPC. Using immunocytochemistry and filipin histochemistry we show that both gangliosides and unesterified cholesterol are differentially stored in neurons of the cerebral cortex, cerebellum, and hippocampus, as well as in liver. Double fluorescence labeling revealed that GM2 ganglioside and unesterified cholesterol were partially co-localized in vesicular structures, and triple fluorescence labeling utilizing a LAMP-1 antibody identified many of these organelles as part of the late endosomal/lysosomal pathway. These observations, coupled with the proposed role of NPC1 in intracellular cholesterol movement, suggest that GM3 and GM2 gangliosides as well as unesterified cholesterol may be retrogradely cleared from late endosomes/lysosomes by an NPC1-dependent mechanism. Cellular consequences of the NPC metabolic defect as shown by parvalbumin immunocytochemistry and rapid Golgi staining, respectively, revealed characteristic axonal spheroids on GABAergic neurons and ectopic dendritogenesis that followed a species-specific gradient of: mouse < feline < human. These studies suggest that the homeostatic regulation of gangliosides and cholesterol in neurons is mediated by NPC1 and that perturbations in this mechanism cause a complex neuronal storage disorder.
AB - Niemann-Pick disease type C (NPC) is a lethal neurologic storage disorder of children most often caused by a defect in the protein NPC1. To better understand the disease we thoroughly characterized the cellular and morphological alterations occurring in murine, feline, and human NPC. Using immunocytochemistry and filipin histochemistry we show that both gangliosides and unesterified cholesterol are differentially stored in neurons of the cerebral cortex, cerebellum, and hippocampus, as well as in liver. Double fluorescence labeling revealed that GM2 ganglioside and unesterified cholesterol were partially co-localized in vesicular structures, and triple fluorescence labeling utilizing a LAMP-1 antibody identified many of these organelles as part of the late endosomal/lysosomal pathway. These observations, coupled with the proposed role of NPC1 in intracellular cholesterol movement, suggest that GM3 and GM2 gangliosides as well as unesterified cholesterol may be retrogradely cleared from late endosomes/lysosomes by an NPC1-dependent mechanism. Cellular consequences of the NPC metabolic defect as shown by parvalbumin immunocytochemistry and rapid Golgi staining, respectively, revealed characteristic axonal spheroids on GABAergic neurons and ectopic dendritogenesis that followed a species-specific gradient of: mouse < feline < human. These studies suggest that the homeostatic regulation of gangliosides and cholesterol in neurons is mediated by NPC1 and that perturbations in this mechanism cause a complex neuronal storage disorder.
KW - Axonal Spheroid
KW - Dendrite
KW - Endosome
KW - Ganglioside
KW - Lysosome
KW - Meganeurite
KW - Unesterified cholesterol
UR - http://www.scopus.com/inward/record.url?scp=0035142802&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035142802&partnerID=8YFLogxK
M3 - Article
C2 - 11202175
AN - SCOPUS:0035142802
VL - 60
SP - 49
EP - 64
JO - American Journal of Psychotherapy
JF - American Journal of Psychotherapy
SN - 0002-9564
IS - 1
ER -