Abstract
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.
Highlights
IntroductionNiemann-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
Our previous work demonstrated that in mouse sympathetic neurons, NPC1 is present in neuronal cell bodies in late endosomes and lysosomes but is abundant in vesicular structures in distal axons [23]. We confirm this observation and show that NPC2 is present in both cell bodies/ proximal axons and distal axons of mouse sympathetic neurons (Fig. 1)
Key questions underlying the molecular basis of Niemann-Pick type C (NPC) disease include the following: Why does the loss of function of a ubiquitously expressed protein affect mainly the central nervous system? And why are neurons vulnerable to the loss of function of NPC1? One feasible explanation for the severe neurological problems in individuals with NPC disease is that NPC1 is expressed in all cell types examined to date, NPC1 might have an additional function in neurons
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. 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 show that NPC1 is abundant in axons of sympathetic neurons and is present in recycling endosomes in presynaptic nerve terminals. Niemann-Pick type C (NPC) disease is a fatal, neurological disease caused in 95% of cases by loss of function of the NPC1 protein. In light of the global alterations of lipid trafficking in all cells lacking functional NPC1, a question arises: Why are neurons so vulnerable to NPC1 deficiency?
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