%0 Journal Article
%T Cholinergic Abnormalities, Endosomal Alterations and Up-Regulation of Nerve Growth Factor Signaling in Niemann-Pick Type C Disease
%A Carolina Cabeza
%A Alicia Figueroa
%A Oscar M Lazo
%A Carolina Galleguillos
%A Claudia Pissani
%A Andr¨¦s Klein
%A Christian Gonzalez-Billault
%A Nibaldo C Inestrosa
%A Alejandra R Alvarez
%A Silvana Zanlungo
%A Francisca C Bronfman
%J Molecular Neurodegeneration
%D 2012
%I BioMed Central
%R 10.1186/1750-1326-7-11
%X NPC1-deficient cholinergic cells respond to NGF after axotomy and exhibit increased levels of choline acetyl transferase (ChAT), whose gene is under the control of NGF signaling, compared to wild type cholinergic neurons. This finding was correlated with increased ChAT and phosphorylated Akt in basal forebrain homogenates. In addition, we found that cholinergic neurons from NPC1-deficient mice had disrupted neuronal morphology, suggesting early signs of neurodegeneration. Consistently, PC12 cells treated with U18666A presented a clear NPC cellular phenotype with a prominent endocytic dysfunction that includes an increased size of TrkA-containing endosomes and reduced recycling of the receptor. This result correlates with increased sensitivity to NGF, and, in particular, with up-regulation of the Akt and PLC-¦Ã signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A.Our results suggest that the NPC cellular phenotype causes neuronal dysfunction through the abnormal up-regulation of survival pathways, which causes the perturbation of signaling cascades and anomalous phosphorylation of the cytoskeleton.Neurotrophins (NGF, BDNF, NT3 and NT4) regulate different aspects of the developing and mature nervous system, including neuronal survival and neuronal morphology. These small proteins exert these effects by binding to members of the Trk family of receptor tyrosine kinases (TrkA, TrkB and TrkC) or to the p75 neurotrophin receptor (p75). Whereas p75 binds all neurotrophins, in addition to other ligands (e.g., proneurotrophins and amyloid peptides), each Trk binds preferentially to its cognate neurotrophin. For example, TrkA, TrkB and TrkC bind NGF, BDNF and NT3, respectively [1-3].Several neurodegenerative diseases are produced by alterations in molecules related to endocytosis and vesicular trafficking, which are cellular processes that regulate neurotrophin signal
%K NGF
%K Endosomes
%K Cholesterol
%K Niemann-Pick type C1
%K cholinergic system
%K PC12
%U http://www.molecularneurodegeneration.com/content/7/1/11