PMID- 34183444 OWN - NLM STAT- MEDLINE DCOM- 20211208 LR - 20211214 IS - 2575-1077 (Electronic) IS - 2575-1077 (Linking) VI - 4 IP - 8 DP - 2021 Aug TI - Increased exosome secretion in neurons aging in vitro by NPC1-mediated endosomal cholesterol buildup. LID - 10.26508/lsa.202101055 [doi] LID - e202101055 AB - 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. CI - (c) 2021 Guix et al. FAU - Guix, Francesc X AU - Guix FX AUID- ORCID: 0000-0001-5781-3799 AD - Molecular Neuropathology Unit, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain fguix@cbm.csic.es fguixrafols@gmail.com. FAU - Capitan, Ana Marrero AU - Capitan AM AD - Molecular Neuropathology Unit, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain. FAU - Casadome-Perales, Alvaro AU - Casadome-Perales A AD - Molecular Neuropathology Unit, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain. FAU - Palomares-Perez, Irene AU - Palomares-Perez I AD - Molecular Neuropathology Unit, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain. FAU - Lopez Del Castillo, Ines AU - Lopez Del Castillo I AD - Molecular Neuropathology Unit, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain. FAU - Miguel, Veronica AU - Miguel V AD - Molecular Pathophysiology of Fibrosis, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain. FAU - Goedeke, Leigh AU - Goedeke L AD - Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA. AD - Integrative Cell Signalling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA. FAU - Martin, Mauricio G AU - Martin MG AD - Instituto de Investigacion Medica Mercedes y Martin Ferreyra (INIMEC)-Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET)-Universidad Nacional de Cordoba (UNC), Cordoba, Argentina. FAU - Lamas, Santiago AU - Lamas S AUID- ORCID: 0000-0001-5166-4155 AD - Molecular Pathophysiology of Fibrosis, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain. FAU - Peinado, Hector AU - Peinado H AD - Microenvironment and Metastasis Group, Molecular Oncology Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. FAU - Fernandez-Hernando, Carlos AU - Fernandez-Hernando C AD - Vascular Biology and Therapeutics Program, Yale University School of Medicine, New Haven, CT, USA. AD - Integrative Cell Signalling and Neurobiology of Metabolism Program, Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA. FAU - Dotti, Carlos G AU - Dotti CG AUID- ORCID: 0000-0003-4052-1719 AD - Molecular Neuropathology Unit, Physiological and Pathological Processes Program, Centro de Biologia Molecular Severo Ochoa, Consejo Superior de Investigaciones Cientificas (CSIC)/Universidad Autonoma de Madrid (UAM), Madrid, Spain cdotti@cbm.csic.es. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210628 PL - United States TA - Life Sci Alliance JT - Life science alliance JID - 101728869 RN - 0 (MIRN33 microRNA, rat) RN - 0 (MicroRNAs) RN - 0 (NPC1 protein, rat) RN - 0 (Niemann-Pick C1 Protein) RN - 97C5T2UQ7J (Cholesterol) SB - IM MH - Animals MH - Cell Line MH - Cellular Senescence MH - Cholesterol/*metabolism MH - Down-Regulation MH - Exosomes/*metabolism MH - HEK293 Cells MH - Humans MH - Mice MH - MicroRNAs/*genetics MH - Multivesicular Bodies/*metabolism MH - Neurons/*cytology/metabolism MH - Niemann-Pick C1 Protein/*genetics MH - Primary Cell Culture MH - Rats MH - Signal Transduction PMC - PMC8321659 COIS- The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2021/06/30 06:00 MHDA- 2021/12/15 06:00 PMCR- 2021/06/28 CRDT- 2021/06/29 05:54 PHST- 2021/02/16 00:00 [received] PHST- 2021/06/11 00:00 [revised] PHST- 2021/06/14 00:00 [accepted] PHST- 2021/06/29 05:54 [entrez] PHST- 2021/06/30 06:00 [pubmed] PHST- 2021/12/15 06:00 [medline] PHST- 2021/06/28 00:00 [pmc-release] AID - 4/8/e202101055 [pii] AID - LSA-2021-01055 [pii] AID - 10.26508/lsa.202101055 [doi] PST - epublish SO - Life Sci Alliance. 2021 Jun 28;4(8):e202101055. doi: 10.26508/lsa.202101055. Print 2021 Aug.