The Niemann-Pick C1 protein in recycling endosomes of presynaptic nerve terminals Published, JLR Papers in Press, December 10, 2005.

Niemann-Pick type C (NPC) disease is a fatal, neurodegenerative disorder caused in 95% of cases by loss of function of NPC1, a ubiquitous endosomal transmembrane protein. A biochemical hallmark of NPC deficiency is cholesterol accumulation in the endocytic pathway. Although cholesterol trafficking defects are observed in all cell types, neurons are the most vulnerable to NPC1 deficiency, suggesting a specialized function for NPC1 in neurons. We investigated the subcellular localization of NPC1 in neurons to gain insight into the mechanism of action of NPC1 in neuronal metabolism. We show that NPC1 is abundant in axons of sympathetic neurons and is present in recycling endosomes in presynaptic nerve terminals. NPC1 deficiency causes morphological and biochemical changes in the presynaptic nerve terminal. Synaptic vesicles from Npc1−/− mice have normal cholesterol content but altered protein composition. We propose that NPC1 plays a previously unrecognized role in the presynaptic nerve terminal and that NPC1 deficiency at this site might contribute to the progressive neurological impairment in NPC disease.

[1]  J. Vance,et al.  Adenovirus expressing an NPC1‐GFP fusion gene corrects neuronal and nonneuronal defects associated with Niemann pick type C disease , 2005, Journal of neuroscience research.

[2]  N. Ohgami,et al.  Niemann-Pick Type C Disease and Intracellular Cholesterol Trafficking* , 2005, Journal of Biological Chemistry.

[3]  G. Francis,et al.  Generation and function of astroglial lipoproteins from Niemann-Pick type C1-deficient mice. , 2005, The Biochemical journal.

[4]  D. Pearce,et al.  CLN3, the protein associated with batten disease: Structure, function and localization , 2005, Journal of neuroscience research.

[5]  R. Maue,et al.  Before the loss: neuronal dysfunction in Niemann-Pick Type C disease. , 2004, Biochimica et biophysica acta.

[6]  M. Patterson,et al.  The pathophysiology and mechanisms of NP-C disease. , 2004, Biochimica et biophysica acta.

[7]  S. Sturley,et al.  Intracellular trafficking of Niemann-Pick C proteins 1 and 2: obligate components of subcellular lipid transport. , 2004, Biochimica et biophysica acta.

[8]  E. Ikonen,et al.  Cellular pathology of Niemann-Pick type C disease. , 2004, Seminars in cell & developmental biology.

[9]  S. Kawamura,et al.  An essential role of Rab5 in uniformity of synaptic vesicle size , 2003, Journal of Cell Science.

[10]  Ann M Stock,et al.  Structure of a cholesterol-binding protein deficient in Niemann–Pick type C2 disease , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[11]  A. Sidow,et al.  The integrity of a cholesterol-binding pocket in Niemann–Pick C2 protein is necessary to control lysosome cholesterol levels , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[12]  R. Campenot,et al.  Trafficking of Cholesterol from Cell Bodies to Distal Axons in Niemann Pick C1-deficient Neurons* , 2003, The Journal of Biological Chemistry.

[13]  D. Mitter,et al.  The synaptophysin/synaptobrevin interaction critically depends on the cholesterol content , 2002, Journal of neurochemistry.

[14]  R. Campenot,et al.  Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann–Pick C1‐deficient neurons , 2002, Journal of neurochemistry.

[15]  K. Higaki,et al.  Accumulation of cholera toxin and GM1 ganglioside in the early endosome of Niemann–Pick C1-deficient cells , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[16]  M. Lehtovirta,et al.  CLN3 protein is targeted to neuronal synapses but excluded from synaptic vesicles: new clues to Batten disease. , 2001, Human molecular genetics.

[17]  S. Walkley,et al.  Critical role for glycosphingolipids in Niemann-Pick disease type C , 2001, Current Biology.

[18]  C. Scriver,et al.  The Metabolic and Molecular Bases of Inherited Disease, 8th Edition 2001 , 2001, Journal of Inherited Metabolic Disease.

[19]  Ta-Yuan Chang,et al.  Fate of Endogenously Synthesized Cholesterol in Niemann-Pick Type C1 Cells* , 2000, The Journal of Biological Chemistry.

[20]  R. Wattiaux,et al.  Identification of HE1 as the second gene of Niemann-Pick C disease. , 2000, Science.

[21]  L. Liscum.  Niemann–Pick Type C Mutations Cause Lipid Traffic Jam , 2000, Traffic.

[22]  Chunjiang Yu,et al.  Role of Niemann-Pick Type C1 Protein in Intracellular Trafficking of Low Density Lipoprotein-derived Cholesterol* , 2000, The Journal of Biological Chemistry.

[23]  W. Volknandt,et al.  Endocytic vacuoles formed following a short pulse of K+-stimulation contain a plethora of presynaptic membrane proteins , 1999, Neuroscience.

[24]  Y. Ioannou,et al.  Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network. , 1999, Molecular genetics and metabolism.

[25]  M. Patterson,et al.  The Niemann-Pick C1 Protein Resides in a Vesicular Compartment Linked to Retrograde Transport of Multiple Lysosomal Cargo* , 1999, The Journal of Biological Chemistry.

[26]  K. Nakashima,et al.  Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile Niemann–Pick disease type C , 1998, Brain and Development.

[27]  W. Pavan,et al.  Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene. , 1997, Science.

[28]  K. G. Coleman,et al.  Niemann-Pick C1 disease gene: homology to mediators of cholesterol homeostasis. , 1997, Science.

[29]  G. Lynch,et al.  Suppression of Cathepsins B and L Causes a Proliferation of Lysosomes and the Formation of Meganeurites in Hippocampus , 1997, The Journal of Neuroscience.

[30]  A. Carvalho,et al.  Membrane potential manipulation in synaptic plasma membrane vesicles for studying neurotransmitter uptake and release. , 1997, Brain research. Brain research protocols.

[31]  R. Parton,et al.  Cell biology of neuronal endocytosis , 1993, Journal of neuroscience research.

[32]  T. Koeda,et al.  Type C Niemann-Pick disease Detection and quantification of cholesterol-accumulating cells in bone marrow , 1993, Brain and Development.

[33]  R. Parton,et al.  Axonal and dendritic endocytic pathways in cultured neurons , 1992, The Journal of cell biology.

[34]  R. Brady,et al.  Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver. , 1992, Biochimica et biophysica acta.

[35]  G. Arthur,et al.  Improved procedures for the determination of lipid phosphorus by malachite green. , 1992, Journal of lipid research.

[36]  A. Chabás,et al.  [Type C Niemann-Pick disease]. , 1991, Sangre.

[37]  W. Gispen,et al.  Ultrastructural double localization of B-50/GAP43 and synaptophysin (p38) in the neonatal and adult rat hippocampus , 1990, Journal of neurocytology.

[38]  R. Kelly,et al.  Biogenesis of synaptic vesicle-like structures in a pheochromocytoma cell line PC-12 , 1990, The Journal of cell biology.

[39]  J. Mendell,et al.  Immunocytochemical evidence for the retrograde transport of intraaxonal cathepsin D: possible relevance to the dying-back process , 1990, Brain Research.

[40]  L. Liscum,et al.  The intracellular transport of low density lipoprotein-derived cholesterol is defective in Niemann-Pick type C fibroblasts , 1989, The Journal of cell biology.

[41]  R. Brady,et al.  Type C Niemann-Pick disease. Lysosomal accumulation and defective intracellular mobilization of low density lipoprotein cholesterol. , 1988, The Journal of biological chemistry.

[42]  J. Rostas,et al.  A rapid Percoll gradient procedure for isolation of synaptosomes directly from an S1 fraction: homogeneity and morphology of subcellular fractions , 1988, Brain Research.

[43]  S. Landis,et al.  Morphological studies of neurotransmitter release and membrane recycling in sympathetic nerve terminals in culture , 1983, Journal of neurocytology.

[44]  S. Landis,et al.  Morphological studies of synapses and varicosities in dissociated cell cultures of sympathetic neurons , 1983, Journal of neurocytology.

[45]  T. Sudhof,et al.  The synaptic vesicle cycle. , 2004, Annual review of neuroscience.

[46]  F. Fahrenholz,et al.  Cholesterol binds to synaptophysin and is required for biogenesis of synaptic vesicles , 1999, Nature Cell Biology.

[47]  A. Spurr.  A low-viscosity epoxy resin embedding medium for electron microscopy. , 1969, Journal of ultrastructure research.