Cholinergic abnormalities, endosomal alterations and up-regulation of nerve growth factor signaling in Niemann-Pick Type C Disease

Carolina Cabeza, Alicia Figueroa, Oscar M. Lazo, Carolina Galleguillos, Claudia Pissani, Andrés Klein, Christian Gonzalez-Billault, Nibaldo C. Inestrosa, Alejandra R. Alvarez, Silvana Zanlungo, Francisca C. Bronfman

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

Background: Neurotrophins and their receptors regulate several aspects of the developing and mature nervous system, including neuronal morphology and survival. Neurotrophin receptors are active in signaling endosomes, which are organelles that propagate neurotrophin signaling along neuronal processes. Defects in the Npc1 gene are associated with the accumulation of cholesterol and lipids in late endosomes and lysosomes, leading to neurodegeneration and Niemann-Pick type C (NPC) disease. The aim of this work was to assess whether the endosomal and lysosomal alterations observed in NPC disease disrupt neurotrophin signaling. As models, we used i) NPC1-deficient mice to evaluate the central cholinergic septo-hippocampal pathway and its response to nerve growth factor (NGF) after axotomy and ii) PC12 cells treated with U18666A, a pharmacological cellular model of NPC, stimulated with NGF. Results: 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- signaling pathways, increased neurite extension, increased phosphorylation of tau protein and cell death when PC12 cells are differentiated and treated with U18666A. Conclusions: 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.

Original languageEnglish
Article number11
JournalMolecular Neurodegeneration
Volume7
Issue number1
DOIs
Publication statusPublished - 30 Mar 2012
Externally publishedYes

Keywords

  • Cholesterol
  • cholinergic system
  • Endosomes
  • NGF
  • Niemann-Pick type C1
  • PC12

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Fingerprint

Dive into the research topics of 'Cholinergic abnormalities, endosomal alterations and up-regulation of nerve growth factor signaling in Niemann-Pick Type C Disease'. Together they form a unique fingerprint.

Cite this