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dc.contributor.advisorMallucci, Giovanna-
dc.contributor.advisorBayliss, Richard-
dc.contributor.advisorBushell, Martin-
dc.contributor.advisorMartins, Luis M.-
dc.contributor.advisorSmith, Andy-
dc.contributor.authorHughes, Daniel T.-
dc.description.abstractNumerous neurodegenerative diseases are characterised by the aggregation of misfolded disease-specific proteins in the brain. This is often associated with increased activation of the unfolded protein response (UPR), particularly the PKR-like Endoplasmic Reticulum Kinase (PERK) branch. PERK is a kinase with endoplasmic reticulum (ER) and cytoplasmic domains. Sustained over-activation of PERK in animal models is neurotoxic and often occurs in the absence of overactivation of the rest of the UPR. PERK inhibition is neuroprotective in mouse prion disease, as well as other neurodegenerative disease models. Systemic PERK inhibition is toxic to the pancreas, but partial modulation of the PERK pathway is neuroprotective without this toxicity. In this thesis, I use biochemical, in vitro and in vivo approaches to 1) address the hypothesis that PERK can be partially modulated in novel ways for neuroprotection. 2) test the hypothesis that the unstructured cytoplasmic loop domain of PERK is involved in non-canonical activation in several of these disorders. The primary study focuses on an inhibitory PERK phosphorylation site (T799), that is a target of Akt. The site was examined for its effects on PERK signalling and its therapeutic potential. The small molecule SC79, which is a specific activator of Akt, increases PERK-P T799 and reduces PERK pathway signalling in in vitro models of ER stress. SC79, when used in vivo reduces PERK-eIF2α signalling in two mouse models of neurodegeneration and increased survival in mouse prion disease. To test the second hypothesis, I used mass spectrometry and phosphoproteomics to characterize the phosphorylation profile and interaction partners of PERK. This revealed new sites of phosphorylation in the cytoplasmic loop of PERK. A new cytoplasmic domain binding-partner, ATAD3A, which exerts an inhibitory effect on PERK signalling, is also characterised. The PERK ‘interactome’ identifies novel binding partners, many of mitochondrial localisation. This prompted ER-mitochondrial contacts to be investigated in disease. Contacts were increased at a critical point in mouse prion disease independently of pathological PERK signalling suggesting they are part of disease pathology and may provide insight into non-canonical PERK signalling during disease.en
dc.rightsCopyright © the author. All rights reserved.en
dc.titleModulation Of PERK Signalling During Neurodegenerationen
dc.publisher.departmentMRC Toxicology Uniten
dc.publisher.institutionUniversity of Leicesteren
Appears in Collections:Leicester Theses
Theses, MRC Toxicology Unit

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