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 d...

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Bibliographic Details
Published inJournal of lipid research Vol. 47; no. 3; pp. 504 - 514
Main Authors Karten, Barbara, Campenot, Robert B, Vance, Dennis E, Vance, Jean E
Format Journal Article
LanguageEnglish
Published United States American Society for Biochemistry and Molecular Biology 01.03.2006
Elsevier
Subjects
Animals
Cells, Cultured
Cerebellum - metabolism
cholesterol
Cholesterol - metabolism
Endosomes - metabolism
Intracellular Signaling Peptides and Proteins
Lipid Metabolism
Lysosomes - metabolism
Mice
Mice, Inbred BALB C
Models, Molecular
Neurons - metabolism
Presynaptic Terminals - metabolism
Proteins - genetics
Proteins - metabolism
synaptic vesicles
Synaptophysin - metabolism
synaptosomes
Transfection
Vesicular Transport Proteins - metabolism
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Summary: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[superscript -/-] 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.
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ISSN:0022-2275
1539-7262
DOI:10.1194/jlr.M500482-JLR200