title: Lack of activation of the unfolded protein response in mouse and cellular models of Niemann-Pick type C disease.
abstract: BACKGROUND
  Niemann-Pick type C (NPC) disease is a fatal lysosomal storage disease related to progressive neurodegeneration secondary to abnormal intracellular accumulation of cholesterol. Signs of endoplasmic reticulum (ER) stress have been reported in other lipidoses. Adaptation to ER stress is mediated by the unfolded protein response (UPR), an integrated signal transduction pathway that attenuates stress or triggers apoptosis of irreversibly damaged cells.
  
  
  OBJECTIVE
  To investigate the possible engagement of ER stress responses in NPC models.
  
  
  METHODS
  We used NPC1 deficient mice and an NPC cell-based model by knocking down the expression of NPC1 to measure several UPR markers through different approaches.
  
  
  RESULTS
  Despite expectations that the UPR will be activated in NPC, our results indicate a lack of ER stress reactions in the cerebellum of symptomatic mice. Similarly, knocking down NPC1 in Neuro2a cells leads to clear cholesterol accumulation without evidence of UPR activation.
  
  
  CONCLUSIONS
  Our results suggest that cholesterol overload and neuronal dysfunction in NPC is not associated with ER stress, which contrasts with recent reports suggesting the activation of the UPR in other lysosomal storage diseases.
authors: Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors: Andres
authors: A
authors: Klein
authors: Matías
authors: M
authors: Mosqueira
authors: Gabriela
authors: G
authors: Martínez
authors: Fermín
authors: F
authors: Robledo
authors: Marcela
authors: M
authors: González
authors: Benjamín
authors: B
authors: Caballero
authors: Gonzalo I
authors: GI
authors: Cancino
authors: Alejandra R
authors: AR
authors: Alvarez
authors: Claudio
authors: C
authors: Hetz
authors: Silvana
authors: S
authors: Zanlungo
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002531:Cerebellum / Q000378:metabolism / Q000473:pathology; D002784:Cholesterol / Q000378:metabolism; D004195:Disease Models, Animal; D004721:Endoplasmic Reticulum / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000378:metabolism / Q000503:physiopathology*; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol