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. CONCLUSION: 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.
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. CONCLUSION: 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: Ute Woehlbier; Alicia Colombo; Mirva J Saaranen; Viviana Pérez; Jorge Ojeda; Fernando J Bustos; Catherine I Andreu; Mauricio Torres; Vicente Valenzuela; Danilo B Medinas; Pablo Rozas; Rene L Vidal; Rodrigo Lopez-Gonzalez; Johnny Salameh; Sara Fernandez-Collemann; Natalia Muñoz; Soledad Matus; Ricardo Armisen; Alfredo Sagredo; Karina Palma; Thergiory Irrazabal; Sandra Almeida; Paloma Gonzalez-Perez; Mario Campero; Fen-Biao Gao; Pablo Henny; Brigitte van Zundert; Lloyd W Ruddock; Miguel L Concha; Juan P Henriquez; Robert H Brown; Claudio Hetz Journal: EMBO J Date: 2016-02-11 Impact factor: 11.598
Authors: Sandra Torres; Elisa Balboa; Silvana Zanlungo; Carlos Enrich; Carmen Garcia-Ruiz; Jose C Fernandez-Checa Journal: Front Physiol Date: 2017-11-30 Impact factor: 4.566