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dc.contributor.authorBordi, Matteo
dc.contributor.authorDarji, Sandipkumar
dc.contributor.authorSato, Yutaka
dc.contributor.authorMellen Rodriguez, Marian
dc.contributor.authorBerg, Martin J.
dc.contributor.authorKumar, Asok
dc.contributor.authorJiang, Ying
dc.contributor.authorNixon, Ralph A.
dc.date.accessioned2019-10-04T11:26:20Z
dc.date.available2019-10-04T11:26:20Z
dc.date.issued2019
dc.identifier.issn2041-4889spa
dc.identifier.urihttp://hdl.handle.net/10641/1684
dc.description.abstractDown syndrome (DS), a complex genetic disorder caused by chromosome 21 trisomy, is associated with mitochondrial dysfunction leading to the accumulation of damaged mitochondria. Here we report that mitophagy, a form of selective autophagy activated to clear damaged mitochondria is deficient in primary human fibroblasts derived from individuals with DS leading to accumulation of damaged mitochondria with consequent increases in oxidative stress. We identified two molecular bases for this mitophagy deficiency: PINK1/PARKIN impairment and abnormal suppression of macroautophagy. First, strongly downregulated PARKIN and the mitophagic adaptor protein SQSTM1/p62 delays PINK1 activation to impair mitophagy induction after mitochondrial depolarization by CCCP or antimycin A plus oligomycin. Secondly, mTOR is strongly hyper-activated, which globally suppresses macroautophagy induction and the transcriptional expression of proteins critical for autophagosome formation such as ATG7, ATG3 and FOXO1. Notably, inhibition of mTOR complex 1 (mTORC1) and complex 2 (mTORC2) using AZD8055 (AZD) restores autophagy flux, PARKIN/PINK initiation of mitophagy, and the clearance of damaged mitochondria by mitophagy. These results recommend mTORC1-mTORC2 inhibition as a promising candidate therapeutic strategy for Down Syndrome.spa
dc.language.isoengspa
dc.publisherCell Death and Diseasespa
dc.rightsAtribución-NoComercial-SinDerivadas 3.0 España*
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/3.0/es/*
dc.subjectDown syndromespa
dc.titlemTOR hyperactivation in Down Syndrome underlies deficits in autophagy induction, autophagosome formation, and mitophagy.spa
dc.typearticlespa
dc.typearticlespa
dc.description.versionpost-printspa
dc.rights.accessRightsopenAccessspa
dc.description.extent3199 KBspa
dc.identifier.doi10.1038/s41419-019-1752-5spa


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Except where otherwise noted, this item's license is described as Atribución-NoComercial-SinDerivadas 3.0 España