The Niemann-Pick C1 protein in recycling endosomes of presynaptic nerve terminals

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. 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. Niemann-Pick type C (NPC) disease is a fatal, neurological disease caused in 95% of cases by loss of function of the NPC1 protein. The remaining 5% of individuals with NPC disease, in whom disease progression is clinically indistinguishable from that caused by mutations in the NPC1 gene, carry a mutation in another gene, NPC2 (also called HE1). The biochemical hallmarks of NPC disease have been described extensively and include an accumulation of unesterified cholesterol and other lipids in the endocytic pathway as well as a reduced ability to respond to changes in cellular cholesterol levels (reviewed in 1Ikonen E. Holtta-Vuori M. Cellular pathology of Niemann-Pick type C disease.Semin. Cell Dev. Biol. 2004; 15: 445-454Google Scholar, 2Chang T.Y. Reid P.C. Sugii S. Ohgami N. Cruz J.C. Chang C.C. Niemann-Pick type C disease and intracellular cholesterol trafficking.J. Biol. Chem. 2005; 280: 20917-20920Google Scholar, 3Liscum L. Niemann-Pick type C mutations cause lipid traffic jam.Traffic. 2000; 1: 218-225Google Scholar). Even though cholesterol homeostasis is disturbed in peripheral tissues, leading to the enlargement of the liver and spleen, the brain is the only organ in which progressive cell death ensues. Consequently, the most devastating symptoms of NPC disease are neurological, including progressive ataxia, cataplexy, supranuclear gaze palsy, and impairment of the swallowing reflex (4Pentchev P.G. Vanier M.T. Suzuki K. Patterson M.C. Niemann-Pick disease type C: a cellular cholesterol lipidosis.in: Beaudet A.L. Scriver C.R. Sly W.S. Valle D. The Metabolic and Molecular Bases of Inherited Disease. McGraw Hill, New York1995: 2625-2639Google Scholar, 5Sturley S.L. Patterson M.C. Balch W. Liscum L. The pathophysiology and mechanisms of NP-C disease.Biochim. Biophys. Acta. 2004; 1685: 83-87Google Scholar). The NPC1 protein is a ubiquitously expressed, transmembrane glycoprotein that localizes to late endosomes/lysosomes but also cycles through the Golgi apparatus (6Neufeld E.B. Wastney M. Patel S. Suresh S. Cooney A.M. Dwyer N.K. Roff C.F. Ohno K. Morris J.A. Carstea E.D. et al.The Niemann-Pick C1 protein resides in a vesicular compartment linked to retrograde transport of multiple lysosomal cargo.J. Biol. Chem. 1999; 274: 9627-9635Google Scholar, 7Higgins M.E. Davies J.P. Chen F.W. Ioannou Y.A. Niemann-Pick C1 is a late endosome-resident protein that transiently associates with lysosomes and the trans-Golgi network.Mol. Genet. Metab. 1999; 68: 1-13Google Scholar). Although the exact function of the NPC1 protein is still unknown, the presence of a sterol-sensing domain in its sequence (8Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. et al.Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.Science. 1997; 277: 232-235Google Scholar, 9Carstea E.D. Morris J.A. Coleman K.G. Loftus S.K. Zhang D. Cummings C. Gu J. Rosenfeld M.A. Pavan W.J. Krizman D.B. et al.Niemann-Pick C1 disease gene: homology to mediators of cholesterol momeostasis.Science. 1997; 277: 228-231Google Scholar) and the accumulation of cholesterol in NPC1-deficient cells (10Sokol J. Blanchette-Mackie E.J. Kruth H.S. Dwyer N.K. Amende L.M. Butler J.D. Robinson E. Patel S. Brady R.O. Comly M.E. et al.Type C Niemann-Pick disease.J. Biol. Chem. 1988; 263: 3411-3417Google Scholar, 11Liscum L. Ruggiero R.M. Faust J.R. The intracellular transport of low density-derived cholesterol is defective in Niemann-Pick type C fibroblasts.J. Cell Biol. 1989; 108: 1625-1636Google Scholar) indicate a role for NPC1 in cholesterol trafficking. NPC2 is a small, soluble, cholesterol binding protein (12Naureckiene S. Sleat D.E. Lackland H. Fensom A. Vanier M.T. Wattiaux R. Jadot M. Lobel P. Identification of HE1 as the second gene of Niemann-Pick C disease.Science. 2000; 290: 2298-2301Google Scholar, 13Friedland N. Liou H.L. Lobel P. Stock A.M. Structure of a cholesterol-binding protein deficient in Niemann-Pick type C2 disease.Proc. Natl. Acad. Sci. USA. 2003; 100: 2512-2517Google Scholar, 14Ko D.C. Binkley J. Sidow A. Scott M.P. The integrity of a cholesterol-binding pocket in Niemann-Pick C2 protein is necessary to control lysosome cholesterol levels.Proc. Natl. Acad. Sci. USA. 2003; 100: 2518-2525Google Scholar) that is widely distributed and, like NPC1, is located in late endosomes/lysosomes (reviewed in 15Liscum L. Sturley S.L. Intracellular trafficking of Niemann-Pick C proteins 1 and 2: obligate components of subcellular lipid transport.Biochim. Biophys. Acta. 2004; 1685: 22-27Google Scholar). The function of NPC2 also remains elusive. The classical model of NPC1 function, as described in cultured NPC1-deficient fibroblasts, involves a role in the egress of endocytosed, lipoprotein-derived cholesterol from lysosomes (10Sokol J. Blanchette-Mackie E.J. Kruth H.S. Dwyer N.K. Amende L.M. Butler J.D. Robinson E. Patel S. Brady R.O. Comly M.E. et al.Type C Niemann-Pick disease.J. Biol. Chem. 1988; 263: 3411-3417Google Scholar, 11Liscum L. Ruggiero R.M. Faust J.R. The intracellular transport of low density-derived cholesterol is defective in Niemann-Pick type C fibroblasts.J. Cell Biol. 1989; 108: 1625-1636Google Scholar, 16Cruz J.C. Sugii S. Yu C. Chang T-Y. Role of Niemann-Pick type C1 protein in intracellular trafficking of low density lipoprotein-derived cholesterol.J. Biol. Chem. 2000; 275: 4013-4021Google Scholar). Additionally, in NPC1-deficient cells, the distribution of cholesterol that has been synthesized endogenously is delayed after its reendocytosis from the plasma membrane (17Cruz J.C. Chang T-Y. Fate of endogenously synthesized cholesterol in Niemann Pick type C1 cells.J. Biol. Chem. 2000; 275: 41309-41316Google Scholar). The trafficking of gangliosides and other glycosphingolipids is also perturbed (18Goldin E. Roff C.F. Miller S.P.F. Rodriguez-Lafrasse C. Vanier M.T. Brady R.O. Pentchev P.G. Type C Niemann-Pick disease: a murine model of the lysosomal cholesterol lipidosis accumulates sphingosine and sphinganine in liver.Biochim. Biophys. Acta. 1992; 1127: 303-311Google Scholar, 19Zervas M. Somers K.L. Thrall M.A. Walkley S.U. Critical role for glycosphingolipids in Niemann-Pick disease type C.Curr. Biol. 2001; 11: 1283-1287Google Scholar, 20Watanabe Y. Akaboshi S. Ishida G. Takeshima T. Yano T. Taniguchi M. Ohno K. Nakashima K. Increased levels of GM2 ganglioside in fibroblasts from a patient with juvenile Niemann-Pick disease type C.Brain Dev. 1998; 20: 95-97Google Scholar). In NPC1-deficient brains, cholesterol is sequestered in late endosomes of glia (21Karten B. Hayashi H. Francis G.A. Campenot R.B. Vance D.E. Vance J.E. Generation and function of astroglial lipoproteins from Niemann-Pick type C1-deficient mice.Biochem. J. 2005; 387: 779-788Google Scholar) as well as in cell bodies of neurons (22Karten B. Vance D.E. Campenot R.B. Vance J.E. Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons.J. Neurochem. 2002; 83: 1154-1163Google Scholar), and impaired anterograde transport of cholesterol in neurons leads to a decrease in the amount of cholesterol in axons (22Karten B. Vance D.E. Campenot R.B. Vance J.E. Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons.J. Neurochem. 2002; 83: 1154-1163Google Scholar, B. Vance D.E. Campenot R.B. Vance J.E. of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.J. Biol. Chem. 2003; Scholar). In of the of lipid trafficking in all cells NPC1, a are neurons vulnerable to NPC1 In have that NPC1 is present only in neuronal cell bodies, late endosomes and lysosomes K. and endocytic in cultured neurons.J. Cell Biol. 1992; Scholar, Cell of neuronal Scholar), but also is abundant in distal axons B. Vance D.E. Campenot R.B. Vance J.E. of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.J. Biol. Chem. 2003; Scholar). vesicles a protein of NPC1 to protein distal axons of sympathetic neurons Reid P.C. B. Zhang M. D. L. Chang T.Y. Vance J.E. et an gene neuronal and defects with Niemann Pick type C disease.J. 2005; Scholar). The role of NPC1 in distal axons is axons are to a site of K. and endocytic in cultured neurons.J. Cell Biol. 1992; Scholar, Cell of neuronal Scholar). We that the presence of NPC1 in axons a function in axons in to the classical role of NPC1 in lipid trafficking from late that NPC1 is present in recycling endosomes in the presynaptic nerve and that a of NPC1 in morphological and biochemical changes in the presynaptic terminal. from cell from nerve from by the of from and from NPC1 a from D. a of of NPC1 and and NPC1 in The NPC1 for a of of NPC1 and by W. S. of The NPC2 a from P. Lobel The from and the membrane from Synaptic from membrane from and from Molecular a Reid P.C. B. Zhang M. D. L. Chang T.Y. Vance J.E. et an gene neuronal and defects with Niemann Pick type C disease.J. 2005; Scholar) by R. A. Reid P.C. B. Zhang M. D. L. Chang T.Y. Vance J.E. et an gene neuronal and defects with Niemann Pick type C disease.J. 2005; Scholar). from 1 from a of mice at the of from with a and with and a mice for the mutation to as Npc1−/− and mice mice for of into with and nerve The at but for which the from by of described previously (8Loftus S.K. Morris J.A. Carstea E.D. Gu J.Z. Cummings C. Brown A. Ellison J. Ohno K. Rosenfeld M.A. Tagle D.A. et al.Murine model of Niemann-Pick C disease: mutation in a cholesterol homeostasis gene.Science. 1997; 277: 232-235Google Scholar). neurons cultured for the of the for at in and in and for at localization of and NPC1, the and NPC1 for and for a with a and neurons for and a of and nerve the as that the and and a of a to the at from a of in and in for in with for as described with as a The from and Npc1−/− mice and of and The remaining in A 1 and with a and at for for with in at to but with to the from a of the and for at The The with and with and for at to in the and proteins from the by The from and Npc1−/− mice and of and density J.A. A for of from an and of subcellular 1988; Scholar). in a in with and for at to and The at for The in and of a of and in B. The in a for at with and from the of the in and by at for in in a with The for for at The at for and the in The of a in plasma membrane vesicles for and 1997; 1: Scholar) of of of and of 5% in at for of the and for at in a from the of the with and for at in a The in and by by NPC1 and and to NPC1 with a of NPC1 proteins by with and with and proteins with and with for NPC2 after of proteins by to with NPC2 in with and with to Synaptic vesicles from the by L. E. R.B. of in a cell Cell Biol. Scholar). the from mice and of and The remaining in a in A with 1 and a at for The at in a for at The and in A and to the of a in in for 1 at in a from the of the and that by for lipid and protein of cholesterol vesicles with the a of and unesterified cholesterol to its by with in for at The by as the The content of vesicles as G. for the of lipid by 1992; Scholar). The amount of protein with the protein with a of and in for in and in for at to and in in for 1 at in of with in for 1 in the and in A for Scholar). with a the distribution of only with Synaptic the domain of The of In late endosomes/lysosomes of the pathway are to to cell bodies K. and endocytic in cultured neurons.J. Cell Biol. 1992; Scholar, Cell of neuronal Scholar). In a of the endosomal in cultured neurons by after with and K. and endocytic in cultured neurons.J. Cell Biol. 1992; Scholar) described endosomal and endosomes in lysosomes and late by after in the cell of that lysosomes to cell bodies E. G. of and causes a of lysosomes and the of in 1997; Scholar). lysosomal as are from axons J.R. for the retrograde transport of to the Scholar), and in sympathetic cholesterol only in cell bodies and J. E. that in sympathetic NPC1 is present only in neuronal cell bodies in late endosomes and lysosomes but is also abundant in vesicular in distal axons B. Vance D.E. Campenot R.B. Vance J.E. of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.J. Biol. Chem. 2003; Scholar). We this and also show that NPC2 is present in cell axons and distal axons of sympathetic neurons NPC2 protein is present in NPC1-deficient neurons in as a to the of to that NPC1 plays a role in axons that the presence of NPC1 in endosomal that are in a pathway. a in the mechanism of action of NPC1 in distal axons, the vesicles that of sympathetic neurons with that NPC1 is to the axons are of recycling and of and in cell of sympathetic neurons.J. Scholar, of and membrane recycling in sympathetic nerve in Scholar), the axons with a protein and NPC1 in the that to binding of sympathetic neurons with a a of NPC1 to has previously been and the of a NPC1 protein that the late endosomal accumulation of cholesterol in Npc1−/− sympathetic neurons Reid P.C. B. Zhang M. D. L. Chang T.Y. Vance J.E. et an gene neuronal and defects with Niemann Pick type C disease.J. 2005; Scholar). neurons with the NPC1 to at with in a to that with NPC1 and but in We investigated NPC1 and the A of in the of to with The with in NPC1 present in the In with the that NPC1 and all NPC1 with a protein and a binding of to the with In the protein in the from the with as a control for A in cell from sympathetic neurons and NPC1 with indicate that a neuronal that NPC1 and in the NPC1 and with to a of a of sympathetic neurons for at to the and in the by for NPC1, and membrane are of with NPC1 present in which nerve from the of and Npc1−/− proteins for The NPC1 protein present in from but Npc1−/− mice is present in recycling endosomes in the presynaptic terminal. from the of type and Npc1−/− mice and by for the presence of The from of the of and Npc1−/− mice a by The and the of the and for NPC1, membrane and C: from mice and at and by a from the of the and for NPC1, and are of with is present in recycling endosomes in the presynaptic terminal. from the of type and Npc1−/− mice and by for the presence of The from of the of and Npc1−/− mice a by The and the of the and for NPC1, membrane and C: from mice and at and by a from the of the and for NPC1, and are of with The presynaptic nerve terminal only vesicles but also and endosomal that in the recycling pathway. vesicles from by L. E. R.B. of in a cell Cell Biol. Scholar) and the localization of NPC1 present in the vesicles NPC1 and the late endosomal protein in the of the NPC1 present in endosomes in the nerve from mice by to vesicles and of the at vesicles in the in the by a from the for NPC1 and for proteins of vesicles endosomes and NPC1 with the endosomal protein as well as with and the remaining and in The in of density and also the endosomal that in the presynaptic nerve NPC1 is present in recycling endosomes but is from for the presence of NPC1 in endosomal in the presynaptic nerve terminal is that NPC1 in the endosomal recycling pathway. NPC1 a role in this might that NPC1 deficiency the of the of NPC1 altered the cholesterol content of vesicles from the of vesicles by that vesicles from the NPC1-deficient a vesicles from that vesicles from Npc1−/− mice a density an with vesicles from the the altered by NPC1 In for and that the amount of to in vesicles from Npc1−/− mice that in vesicles from mice the protein of vesicles from is altered by NPC1 of vesicles from and Npc1−/− vesicles from the of type and Npc1−/− mice by a and by for C: and for cholesterol and are from Synaptic vesicles from Npc1−/− by with of cholesterol and by for and are of with with of vesicles from and Npc1−/− vesicles from the of type and Npc1−/− mice by a and by for C: and for cholesterol and are from Synaptic vesicles from Npc1−/− by with of cholesterol and by for and are of with with of vesicles from and Npc1−/− vesicles from the of type and Npc1−/− mice by a and by for C: and for cholesterol and are from Synaptic vesicles from Npc1−/− by with of cholesterol and by for and are of with with the of vesicles by NPC1 deficiency, the protein of the presynaptic terminal as a from the of and Npc1−/− mice and by for proteins of in the nerve which is present in the plasma membrane of nerve M. localization of and in the and Scholar) but is in as a The of the proteins and by NPC1 the in vesicles from Npc1−/− mice is a of an altered distribution of proteins of a in of of proteins in the presynaptic terminal. with from and from Npc1−/− are in the late protein in the late endosomal protein NPC2 is also by NPC1 deficiency with the that NPC2 in distal axons is by NPC1 deficiency and morphological changes in NPC1-deficient presynaptic terminals. from the of type and Npc1−/− mice and for NPC1, and as a from and Npc1−/− mice in and with and and in by are of C: to vesicles in with an membrane into The of vesicles of The of vesicles for and for Npc1−/− from and morphological changes in NPC1-deficient presynaptic terminals. from the of type and Npc1−/− mice and for NPC1, and as a from and Npc1−/− mice in and with and and in by are of C: to vesicles in with an membrane into The of vesicles of The of vesicles for and for Npc1−/− from of by vesicles In Npc1−/− a of vesicular that observed in Although the distribution of the of vesicles in Npc1−/− and with the a of Npc1−/− a of vesicles with of that NPC1 is present in recycling endosomes of the presynaptic terminal. The of NPC1 leads to morphological changes in the presynaptic terminal and in the protein of a in NPC disease, the exact of NPC1 and NPC2 elusive. the of NPC disease include the the loss of function of a ubiquitously protein the are neurons vulnerable to the loss of function of for the neurological in individuals with NPC disease is that NPC1 is in all cell to NPC1 might have an function in neurons. is that peripheral cells, but a pathway that for NPC1 the function of NPC1 might the in all cell types, but neurons might to the loss of NPC1 the that NPC1 plays a role in to its role in all cells, that NPC1 is present in distal We show that NPC1 and NPC2 are present in distal axons of sympathetic the NPC1 protein is located in in distal axons and extensively with the a of endosomal vesicles in NPC1 and and vesicles are to recycling endosomes in the presynaptic nerve vesicles from Npc1−/− mice have normal of cholesterol and but in and protein with vesicles from and NPC1-deficient a of that NPC1 is necessary to the of the presynaptic nerve In the model of NPC1 function, NPC1 is in cholesterol other lipids from late endosomes and lysosomes to the and plasma are with this model in that cholesterol accumulates late endosomes/lysosomes in cell bodies of Npc1−/− neurons but is in axons (22Karten B. Vance D.E. Campenot R.B. Vance J.E. Cholesterol accumulates in cell bodies, but is decreased in distal axons, of Niemann-Pick C1-deficient neurons.J. Neurochem. 2002; 83: 1154-1163Google Scholar) and the of cholesterol from cell bodies to distal axons is impaired B. Vance D.E. Campenot R.B. Vance J.E. of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.J. Biol. Chem. 2003; Scholar). In late endosomes and lysosomes are to cell bodies K. and endocytic in cultured neurons.J. Cell Biol. 1992; Scholar, Cell of neuronal Scholar). We that NPC1 and NPC2 are present only in cell bodies but also in distal axons B. Vance D.E. Campenot R.B. Vance J.E. of cholesterol from cell bodies to distal axons in Niemann Pick C1-deficient neurons.J. Biol. Chem. 2003; Scholar) We that NPC1 might a role in distal axons the distribution of lipids of late to NPC1 extensively with and is most abundant in and the In NPC1 is in from NPC1 is a of vesicles is a of endosomes in the nerve terminal. the that NPC1 is in neuronal another causes the neurological lysosomal disease juvenile neuronal (reviewed in D.A. the protein with disease: function and 2005; Scholar), but function is as unknown, has been in recycling endosomes of the presynaptic terminal K. M. A. protein is to neuronal but from to Genet. 2001; Scholar). from the presynaptic terminal involves a of (reviewed in The 2004; Scholar), of which are in which a nerve a with In this vesicles are with by The amount of is by the of the The with the plasma and after and the of vesicles are with by vesicles and with remaining vesicles but to the are and with as in vesicles and with after after through an endosomal indicate that NPC1 is present in this endosomal The endosomal recycling pathway is the other mechanisms that but is to have the other and to for a of The 2004; Scholar). NPC1 in the endosomal recycling of NPC1 might to a of the of a but might for of the progressive neurological the of an with NPC disease. and changes in the of Npc1−/− cells have been the neuronal in Niemann-Pick type C disease.Biochim. Biophys. Acta. 2004; 1685: Scholar). recycling might also a control mechanism for the of defective vesicles from the recycling through the The 2004; Scholar). NPC1 a role in this control changes in in the of in nerve from NPC1-deficient altered protein of vesicles and the presence of vesicles in the nerve terminal. The of to that observed in vesicles from Npc1−/− mice an to cholesterol metabolism. is a cholesterol binding protein C. Cholesterol to and is for of Cell Biol. 2000; 2: Scholar) that to to membrane D. C. B. S. S. A. G. The the cholesterol Neurochem. 2003; Scholar) and a with the of vesicles to the presynaptic plasma membrane The 2004; Scholar). of a the cholesterol content of the membrane and to reduced in the of with mice D. C. B. S. S. A. G. The the cholesterol Neurochem. 2003; Scholar). We that NPC1 cholesterol in the nerve the of into vesicles and its with The of the vesicles that observed by of NPC1-deficient is vesicles are to vesicles that have the control mechanism that involves in the endosomal proteins and NPC2 are by NPC1 deficiency, the that vesicles an of recycling endosomes in the presynaptic terminal M. W. H. a of a of presynaptic membrane 1999; Scholar). a of endosomes might a mechanism for NPC1 deficiency in the vesicles might vesicles that have from from changes in membrane by recycling through an NPC1-deficient The of vesicles has been linked to function H. S. K. role of in of Cell Sci. 2003; Scholar), and a deficient recycling of ganglioside from endosomes to the plasma membrane has been observed in NPC1-deficient fibroblasts Y. H. Y. K. Davies J.P. Ioannou Y.A. Ohno K. of and ganglioside in the of Niemann-Pick C1-deficient Natl. Acad. Sci. USA. 2001; Scholar). In that NPC1 is present in endosomes in the presynaptic terminal of neurons. The of NPC1 causes morphological changes in the presynaptic nerve as well as in the of a role for NPC1 in the recycling in to its role in cholesterol from late might contribute to the neurological of NPC1 disease. The and for and Chen for in for by from the and the for to the of a from the for is a of the and of the in the Molecular and Cell of protein membrane protein Niemann-Pick type C membrane protein

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