TY - JOUR
T1 - Consequences of NPC1 and NPC2 loss of function in mammalian neurons
AU - Walkley, Steven U.
AU - Suzuki, Kinuko
N1 - Funding Information:
The authors would like to thank our many colleagues as well as current and past members of our laboratories who have so generously helped us in the study of Niemann–Pick disease type C. The murine NPC2 studies referred to were part of a collaborative effort between one of us (SUW) and Drs. D. Sleat and P. Lobel, who are gratefully acknowledged. We thank the National Institutes of Health and the Ara Parseghian Medical Research Foundation for grant support.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2004/10/11
Y1 - 2004/10/11
N2 - Genetic deficiency of NPC1 or NPC2 results in a devastating cholesterol-glycosphingolipidosis of brain and other organs known as Niemann - Pick type C (NPC) disease. While NPC1 is a transmembrane protein believed involved in retroendocytic shuttling of substrate(s) to the Golgi and possibly elsewhere in cells as part of an essential recycling/homeostatic control mechanism, NPC2 is a soluble lysosomal protein known to bind cholesterol. The precise role(s) of NPC1 and NPC2 in endosomala-lysosomal function remain unclear, nor is it known whether the two proteins directly interact as part of this function. The pathologic features of NPC disease, however, are well documented. Brain cells undergo massive intracellular accumulation of glycosphingolipids (lactosylceramide, glucosylceramide, GM2 and GM3 gangliosides) and cholesterol and concomitant distortion of neuron shape (meganeurite formation). In neurons from humans with NPC disease the metabolic defects and storage often lead to extensive growth of new, ectopic dendrites (possibly linked to ganglioside sequestration) as well as formation of neurofibrillary tangles (NFTs) (possibly linked to dysregulation of cholesterol metabolism). Other features of cellular pathology in NPC disease include fragmentation of the Golgi apparatus and neuroaxonal dystrophy, though reasons for these changes remain largely unknown. As the disease progresses, neurodegeneration is also apparent for neurons in some brain regions, particularly Purkinje cells of the cerebellum, but the basis of this selective neuronal vulnerability is unknown. The NPC1 protein is evolutionarily conserved with homologues reported in yeast to humans; NPC2 is reported in C. elegans to humans. While neurons in mammalian models of NPC1 and NPC2 diseases exhibit many changes that are remarkably similar to those in humans (e.g., endosomal/lysosomal storage, Golgi fragmentation, neuroaxonal dystrophy, neurodegeneration), a reduced degree of ectopic dendritogenesis and an absence of NFTs in these species suggest important differences in the way lower mammalian neurons respond to NPC1/NPC2 loss of function.
AB - Genetic deficiency of NPC1 or NPC2 results in a devastating cholesterol-glycosphingolipidosis of brain and other organs known as Niemann - Pick type C (NPC) disease. While NPC1 is a transmembrane protein believed involved in retroendocytic shuttling of substrate(s) to the Golgi and possibly elsewhere in cells as part of an essential recycling/homeostatic control mechanism, NPC2 is a soluble lysosomal protein known to bind cholesterol. The precise role(s) of NPC1 and NPC2 in endosomala-lysosomal function remain unclear, nor is it known whether the two proteins directly interact as part of this function. The pathologic features of NPC disease, however, are well documented. Brain cells undergo massive intracellular accumulation of glycosphingolipids (lactosylceramide, glucosylceramide, GM2 and GM3 gangliosides) and cholesterol and concomitant distortion of neuron shape (meganeurite formation). In neurons from humans with NPC disease the metabolic defects and storage often lead to extensive growth of new, ectopic dendrites (possibly linked to ganglioside sequestration) as well as formation of neurofibrillary tangles (NFTs) (possibly linked to dysregulation of cholesterol metabolism). Other features of cellular pathology in NPC disease include fragmentation of the Golgi apparatus and neuroaxonal dystrophy, though reasons for these changes remain largely unknown. As the disease progresses, neurodegeneration is also apparent for neurons in some brain regions, particularly Purkinje cells of the cerebellum, but the basis of this selective neuronal vulnerability is unknown. The NPC1 protein is evolutionarily conserved with homologues reported in yeast to humans; NPC2 is reported in C. elegans to humans. While neurons in mammalian models of NPC1 and NPC2 diseases exhibit many changes that are remarkably similar to those in humans (e.g., endosomal/lysosomal storage, Golgi fragmentation, neuroaxonal dystrophy, neurodegeneration), a reduced degree of ectopic dendritogenesis and an absence of NFTs in these species suggest important differences in the way lower mammalian neurons respond to NPC1/NPC2 loss of function.
KW - Axonal spheroid
KW - Dendritogenesis
KW - Endosome
KW - Golgi fragmentation
KW - Lysosome
KW - Neurodegeneration
KW - Neurofibrillary tangle
KW - Niemann - Pick type C
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U2 - 10.1016/j.bbalip.2004.08.011
DO - 10.1016/j.bbalip.2004.08.011
M3 - Review article
C2 - 15465426
AN - SCOPUS:4744365602
SN - 1388-1981
VL - 1685
SP - 48
EP - 62
JO - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
JF - Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
IS - 1-3
ER -