Lack of activation of the unfolded protein response in mouse and cellular models of Niemann-Pick type C disease.
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.
Klein
Andres
A
Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile.
Mosqueira
Matías
M
Martínez
Gabriela
G
Robledo
Fermín
F
González
Marcela
M
Caballero
Benjamín
B
Cancino
Gonzalo I
GI
Alvarez
Alejandra R
AR
Hetz
Claudio
C
Zanlungo
Silvana
S
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*
D047908:Intracellular Signaling Peptides and Proteins; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D002784:Cholesterol