title: Inactivation of Apaf1 reduces the formation of mutant huntingtin-dependent aggregates and cell death.
abstract: Polyglutamine expansions in some proteins associated with neurodegenerative diseases, such as Huntington's disease or several ataxias, lead to insoluble aggregates in the cell. These aggregates accumulate through a mechanism that is not yet fully understood, but it activates cell death pathways and contributes to kill the cell. Here, we show that apoptotic protease activating factor 1 (Apaf1) down-regulation, or treatment with pharmacological Apaf1 inhibitor SVT016426, decreases both polyglutamine-induced aggregation and polyglutamine-induced apoptotic cell death in different cellular models. We demonstrate that Apaf1 binds to both Htt and to heat shock protein chaperone Hsp70, and that this interaction is altered in the presence of the pharmacological inhibitor of Apaf1. Based on our findings, we hypothesize that Apaf1 enhances polyglutamine aggregation by reducing the cellular protein levels of available functional Hsp70.
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Sancho
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain.
authors.forename: A E
authors.initials: AE
authors.lastname: Herrera
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain. Electronic address: morzaez@cipf.es.
authors.forename: M
authors.initials: M
authors.lastname: Orzáez
authors.affiliation: Laboratory of Peptide and Protein Chemistry, Centro de Investigación Príncipe Felipe, E-46012 Valencia, Spain; Instituto de Biomedicina de Valencia, IBV-CSIC, E-46010 Valencia, Spain.
authors.forename: E
authors.initials: E
authors.lastname: Pérez-Payá
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology; D005347:Fibroblasts; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000378:metabolism*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism*
chemical_list: C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D018840:HSP70 Heat-Shock Proteins; C086055:HTT protein, human; D006571:Heterocyclic Compounds; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D050486:Serotonin Plasma Membrane Transport Proteins; C493231:Slc6a4 protein, mouse; C097188:polyglutamine
keywords: Apaf1; Huntington’s disease; huntingtin; polyglutamines