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dc.contributor.advisor | Priori, Silvia G. | |
dc.contributor.advisor | Castillo Demetrio Julián, Santiago | |
dc.contributor.author | Cancemi, Andrea | |
dc.date.accessioned | 2022-03-02T12:12:21Z | |
dc.date.available | 2022-03-02T12:12:21Z | |
dc.date.issued | 2021-11-19 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/13710 | |
dc.description.abstract | Calcium transients between the Sarcoplasmic Reticulum (SR) and the cytoplasm are essential for coordinated contraction in cardiomyocytes. Loss of the SR protein Calsequestrin 2 (CASQ2) causes the recessive form of Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT2) by increasing the diastolic opening probability of the main SR calcium channel Ryanodine receptor 2 (RyR2), and by causing an unexplained decrease of its regulatory protein Triadin (TRDN). Here we studied the mechanisms of TRDN reduction in CASQ2-KO mice and show that ablation of CASQ2 activates histone-deacetylase HDAC6, which regulates several cellular processes. In CASQ2 deficient cardiomyocytes, HDAC6 reduces alpha-Tubulin acetylation, thus impairing microtubule stability and altering TRDN trafficking and co-localization with RyR2. Misplaced TRDN binds HSP70, forming Aggresomes that are degraded by autophagy. The study identifies a novel cascade of post-transcriptional events initiated by the loss of CASQ2 that leads to a major rearrangement of SR protein trafficking and stability in cardiomyocytes | es_ES |
dc.language.iso | eng | es_ES |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-sa/4.0/ | * |
dc.subject | inherited arrhythmias | es_ES |
dc.subject | CpvT | es_ES |
dc.subject | Microtubulus | es_ES |
dc.subject | autophagy | es_ES |
dc.title | Cytoskeletal remodeling and enhanced autophagy drive an adaptive response to loss of Calsequestrin in a model of inherited arrhythmias | es_ES |
dc.type | doctoral thesis | es_ES |
dc.rights.license | Atribución-NoComercial-CompartirIgual 4.0 Internacional | * |
dc.identifier.doi | 10.4321/repisalud.13710 | |
dc.description.peerreviewed | No | es_ES |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Cardiología Molecular | es_ES |
dc.repisalud.institucion | CNIC | es_ES |
dc.rights.accessRights | open access | es_ES |