Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup
| Autor: | Héctor Peinado, Verónica Miguel, Francesc X. Guix, Santiago Lamas, Mauricio G. Martin, Álvaro Casadomé-Perales, Inés López del Castillo, Ana Marrero Capitán, Irene Palomares-Pérez, Carlos G. Dotti, Leigh Goedeke, Carlos Fernández-Hernando |
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| Přispěvatelé: | European Commission, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, Comunidad de Madrid, Consejo Superior de Investigaciones Científicas (España) |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Endosome Health Toxicology and Mutagenesis Primary Cell Culture Down-Regulation Plant Science Exosomes Biochemistry Genetics and Molecular Biology (miscellaneous) Exosome Cell Line 03 medical and health sciences Mice 0302 clinical medicine Downregulation and upregulation Niemann-Pick C1 Protein Animals Humans Secretion Research Articles Cellular Senescence Phagosome Neurons Ecology Chemistry Vesicle Multivesicular Bodies Microvesicles Cell biology Rats MicroRNAs 030104 developmental biology Cholesterol HEK293 Cells NPC1 030217 neurology & neurosurgery Research Article Signal Transduction |
| Zdroj: | Digital.CSIC. Repositorio Institucional del CSIC instname Life Science Alliance |
| Popis: | The present study unveils the molecular mechanism through which neurons in vitro compensate age-associated proteostasis defects by increasing exosome release. As neurons age, they show a decrease in their ability to degrade proteins and membranes. Because undegraded material is a source of toxic products, defects in degradation are associated with reduced cell function and survival. However, there are very few dead neurons in the aging brain, suggesting the action of compensatory mechanisms. We show in this work that ageing neurons in culture show large multivesicular bodies (MVBs) filled with intralumenal vesicles (ILVs) and secrete more small extracellular vesicles than younger neurons. We also show that the high number of ILVs is the consequence of the accumulation of cholesterol in MVBs, which in turn is due to decreased levels of the cholesterol extruding protein NPC1. NPC1 down-regulation is the consequence of a combination of upregulation of the NPC1 repressor microRNA 33, and increased degradation, due to Akt-mTOR targeting of NPC1 to the phagosome. Although releasing more exosomes can be beneficial to old neurons, other cells, neighbouring and distant, can be negatively affected by the waste material they contain. |
| Databáze: | OpenAIRE |
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