Evaluation of selective γ-secretase inhibitors as novel modulators of TNF-α-mediated apoptosis

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dc.availability.bitstreamcontrolled
dc.check.date2022-05-30
dc.contributor.advisorMcCarthy, Justin V.en
dc.contributor.authorO'Brien, Ciara
dc.contributor.funderScience Foundation Irelanden
dc.date.accessioned2021-05-24T11:26:17Z
dc.date.available2021-05-24T11:26:17Z
dc.date.issued2021-05-04
dc.date.submitted2021-05-04
dc.description.abstractThe 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.en
dc.description.statusNot peer revieweden
dc.description.versionAccepted Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationO'Brien, C. 2020. Evaluation of selective γ-secretase inhibitors as novel modulators of TNF-α-mediated apoptosis. MRes Thesis, University College Cork.en
dc.identifier.endpage91en
dc.identifier.urihttps://hdl.handle.net/10468/11373
dc.language.isoenen
dc.publisherUniversity College Corken
dc.rights© 2021, Ciara O'Brien.en
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectTNF-alphaen
dc.subjectAlzheimer's Diseaseen
dc.subjectApoptosisen
dc.subjectPresenilinsen
dc.subjecty-Secretaseen
dc.subjecty-Secretase inhibitorsen
dc.titleEvaluation of selective γ-secretase inhibitors as novel modulators of TNF-α-mediated apoptosisen
dc.typeMasters thesis (Research)en
dc.type.qualificationlevelMastersen
dc.type.qualificationnameMSc - Master of Scienceen
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