{"id":{"repo_id":"cork","oai_identifier":"oai:cora.ucc.ie:10468/11373"},"canonical_url":"https://search.dev.ndltd.org/etd/cork/oai:cora.ucc.ie:10468/11373","repository":{"repo_id":"cork","name":"University College Cork","base_url":"https://cora.ucc.ie/server/oai/request"},"display":{"title":"Evaluation of selective γ-secretase inhibitors as novel modulators of TNF-α-mediated apoptosis","abstract":"The presenilin proteins (presenilin 1 and presenilin 2) were identified in mutagenesis screens causing the early onset forms of familial Alzheimer’s disease (FAD) in 1995. Subsequently characterized as the catalytic subunits of the γ-secretase protease complexes, the presenilins are responsible for the cleavage of the amyloid precursor protein (APP) and generation of amyloid beta (Aβ). To date, γ-secretase proteases have over 120 substrates which demonstrate contribution to a diverse range of cellular processes and signalling events. However, recent findings have revealed several γ-secretase-independent presenilin functions, including calcium signalling, autophagy and apoptosis. We and others have previously reported members of the TNF receptor super-family as substrates for γ-secretase proteolysis, and that presenilin-deficient cells have increased resistance to TNFα-induced apoptosis. In this study, we sought to determine whether loss of presenilin expression or loss of γ-secretase protease activity is associated with increased resistance to TNFα-induced apoptosis. Utilizing the cleavage of caspase 3 and Poly ADP ribose polymerase (PARP) in target cells as a readout, we tested the anti-apoptotic characteristics of a panel of well characterized γ-secretase inhibitors. In this study, we show that loss of presenilin expression is associated with increased resistance to TNFα-induced apoptosis, and that loss of γ-secretase protease activity does not affect sensitivity to TNFα-induced apoptosis. These observations suggest a γ-secretase-independent role of presenilins in the regulation of TNFα-induced apoptosis.","abstract_html":"The presenilin proteins (presenilin 1 and presenilin 2) were identified in mutagenesis screens causing the early onset forms of familial Alzheimer’s disease (FAD) in 1995. Subsequently characterized as the catalytic subunits of the γ-secretase protease complexes, the presenilins are responsible for the cleavage of the amyloid precursor protein (APP) and generation of amyloid beta (Aβ). To date, γ-secretase proteases have over 120 substrates which demonstrate contribution to a diverse range of cellular processes and signalling events. However, recent findings have revealed several γ-secretase-independent presenilin functions, including calcium signalling, autophagy and apoptosis. We and others have previously reported members of the TNF receptor super-family as substrates for γ-secretase proteolysis, and that presenilin-deficient cells have increased resistance to TNFα-induced apoptosis. In this study, we sought to determine whether loss of presenilin expression or loss of γ-secretase protease activity is associated with increased resistance to TNFα-induced apoptosis. Utilizing the cleavage of caspase 3 and Poly ADP ribose polymerase (PARP) in target cells as a readout, we tested the anti-apoptotic characteristics of a panel of well characterized γ-secretase inhibitors. In this study, we show that loss of presenilin expression is associated with increased resistance to TNFα-induced apoptosis, and that loss of γ-secretase protease activity does not affect sensitivity to TNFα-induced apoptosis. These observations suggest a γ-secretase-independent role of presenilins in the regulation of TNFα-induced apoptosis.","abstract_has_math":false,"creators":["O'Brien, Ciara"],"institution":"University College Cork","degree_name":null,"degree_level":null,"degree_discipline":null,"degree_department":null,"school":null,"contributors":[],"advisors":["McCarthy, Justin V."],"committee_chairs":[],"committee_members":[],"year":2021,"date_issued":"2021-05-04","date_published":"2021-05-04","updated_at":"2026-07-24T01:46:44Z","subjects":["TNF-alpha","Alzheimer's Disease","Apoptosis","Presenilins","y-Secretase","y-Secretase inhibitors"],"languages":["en"],"rights":["© 2021, Ciara O'Brien."],"rights_urls":["https://creativecommons.org/licenses/by-nc-nd/4.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/10468/11373","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["McCarthy, Justin V."]},{"key":"dc:creator","label":"Author","values":["O'Brien, Ciara"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.accessioned","label":"Dc Date Accessioned","values":["2021-05-24T11:26:17Z"]},{"key":"dc:date.available","label":"Dc Date Available","values":["2021-05-24T11:26:17Z"]},{"key":"dc:date.issued","label":"Date","values":["2021-05-04"]},{"key":"dc:publisher","label":"Institution","values":["University College Cork"]},{"key":"dc:type","label":"Dc Type","values":["Masters thesis (Research)"]},{"key":"dc:type.qualificationlevel","label":"Dc Type Qualificationlevel","values":["Masters"]},{"key":"dc:type.qualificationname","label":"Dc Type Qualificationname","values":["MSc - Master of Science"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["TNF-alpha","Alzheimer's Disease","Apoptosis","Presenilins","y-Secretase","y-Secretase inhibitors"]}]},{"id":"language_rights","label":"Language and Rights","entries":[{"key":"dc:language.iso","label":"Language (ISO)","values":["en"]},{"key":"dc:rights","label":"Dc Rights","values":["© 2021, Ciara O'Brien."]},{"key":"dc:rights.uri","label":"Rights URI","values":["https://creativecommons.org/licenses/by-nc-nd/4.0/"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier.uri","label":"Identifier URI","values":["https://hdl.handle.net/10468/11373"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["The presenilin proteins (presenilin 1 and presenilin 2) were identified in mutagenesis screens causing the early onset forms of familial Alzheimer’s disease (FAD) in 1995. Subsequently characterized as the catalytic subunits of the γ-secretase protease complexes, the presenilins are responsible for the cleavage of the amyloid precursor protein (APP) and generation of amyloid beta (Aβ). To date, γ-secretase proteases have over 120 substrates which demonstrate contribution to a diverse range of cellular processes and signalling events. However, recent findings have revealed several γ-secretase-independent presenilin functions, including calcium signalling, autophagy and apoptosis. We and others have previously reported members of the TNF receptor super-family as substrates for γ-secretase proteolysis, and that presenilin-deficient cells have increased resistance to TNFα-induced apoptosis. In this study, we sought to determine whether loss of presenilin expression or loss of γ-secretase protease activity is associated with increased resistance to TNFα-induced apoptosis. Utilizing the cleavage of caspase 3 and Poly ADP ribose polymerase (PARP) in target cells as a readout, we tested the anti-apoptotic characteristics of a panel of well characterized γ-secretase inhibitors. In this study, we show that loss of presenilin expression is associated with increased resistance to TNFα-induced apoptosis, and that loss of γ-secretase protease activity does not affect sensitivity to TNFα-induced apoptosis. These observations suggest a γ-secretase-independent role of presenilins in the regulation of TNFα-induced apoptosis."]},{"key":"dc:format.mimetype","label":"Dc Format Mimetype","values":["application/pdf"]},{"key":"dc:title","label":"Title","values":["Evaluation of selective γ-secretase inhibitors as novel modulators of TNF-α-mediated apoptosis"]}]}],"canonical_facts":{"dc:contributor.advisor":["McCarthy, Justin V."],"dc:creator":["O'Brien, Ciara"],"dc:date.accessioned":["2021-05-24T11:26:17Z"],"dc:date.available":["2021-05-24T11:26:17Z"],"dc:date.issued":["2021-05-04"],"dc:description.abstract":["The presenilin proteins (presenilin 1 and presenilin 2) were identified in mutagenesis screens causing the early onset forms of familial Alzheimer’s disease (FAD) in 1995. Subsequently characterized as the catalytic subunits of the γ-secretase protease complexes, the presenilins are responsible for the cleavage of the amyloid precursor protein (APP) and generation of amyloid beta (Aβ). To date, γ-secretase proteases have over 120 substrates which demonstrate contribution to a diverse range of cellular processes and signalling events. However, recent findings have revealed several γ-secretase-independent presenilin functions, including calcium signalling, autophagy and apoptosis. We and others have previously reported members of the TNF receptor super-family as substrates for γ-secretase proteolysis, and that presenilin-deficient cells have increased resistance to TNFα-induced apoptosis. In this study, we sought to determine whether loss of presenilin expression or loss of γ-secretase protease activity is associated with increased resistance to TNFα-induced apoptosis. Utilizing the cleavage of caspase 3 and Poly ADP ribose polymerase (PARP) in target cells as a readout, we tested the anti-apoptotic characteristics of a panel of well characterized γ-secretase inhibitors. In this study, we show that loss of presenilin expression is associated with increased resistance to TNFα-induced apoptosis, and that loss of γ-secretase protease activity does not affect sensitivity to TNFα-induced apoptosis. These observations suggest a γ-secretase-independent role of presenilins in the regulation of TNFα-induced apoptosis."],"dc:format.mimetype":["application/pdf"],"dc:identifier.uri":["https://hdl.handle.net/10468/11373"],"dc:language.iso":["en"],"dc:publisher":["University College Cork"],"dc:rights":["© 2021, Ciara O'Brien."],"dc:rights.uri":["https://creativecommons.org/licenses/by-nc-nd/4.0/"],"dc:subject":["TNF-alpha","Alzheimer's Disease","Apoptosis","Presenilins","y-Secretase","y-Secretase inhibitors"],"dc:title":["Evaluation of selective γ-secretase inhibitors as novel modulators of TNF-α-mediated apoptosis"],"dc:type":["Masters thesis (Research)"],"dc:type.qualificationlevel":["Masters"],"dc:type.qualificationname":["MSc - Master of Science"]},"updated_at":"2026-07-24T01:46:44Z"}