| Autor: |
Hecimovic, Silva, Dominko, Kristina, Rastija, Ana, Meglaj, Sarah, Vidatić, Lea, Babić, Andrea, Colombo, Alessio, Tahirovic, Sabina |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Popis: |
It is intriguing that Niemann-Pick type C disease (NPC) shares several features with Alzheimer’s disease (AD), including enhanced levels of amyloid-β peptides (Aβ) due to enhanced β-amyloid precursor protein (APP) cleavage by BACE1, a key enzyme in the pathogenesis of AD. Since retromer complex is responsible for APP and BACE1 retrieval out of endosomes, thus preventing Aβ formation, in this work we tested the hypothesis that increased amyloidogenic processing of APP and enhanced BACE1-mediated proteolysis in NPC disease involves retromer dysfunction, indicating that retromer impairment may be involved in the pathogenesis of NPC. This is supported by the recent finding of the link between intracellular cholesterol transport and retromer function and the role of phosphoinositides in this process. Using NPC1-null cells, mouse NPC1 primary neurons and NPC1 mice we show that retromer function is impaired in NPC disease. It is characterized by altered transport of the retromer core components Vps26, Vps35 and/or retromer receptor sorLA and by retromer accumulation in neuronal processes and within axonal swellings. Changes in retromer distribution in NPC1 mouse brains were observed already at presymptomatic stage (at 4-weeks of age), indicating that retromer defect occurs early in the course of NPC disease and may contribute to downstream pathological processes. Furthermore, we showed that cholesterol depletion in NPC1-null cells and in NPC1 mouse brains reverts retromer dysfunction, suggesting that retromer impairment in NPC is dependent on cholesterol accumulation. Thus, we characterize retromer dysfunction in NPC and propose that rescue of retromer impairment may represent a novel therapeutic approach against NPC. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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