Characterising CG5846 (Peep) in Drosophila melanogaster neural function : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Manawatū, New Zealand

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dc.confidentialEmbargo : No
dc.contributor.advisorFitzsimons, Helen
dc.contributor.authorWilson, Sarah Jean
dc.date.accessioned2024-08-13T03:54:56Z
dc.date.available2024-08-13T03:54:56Z
dc.date.issued2024
dc.description.abstractHistone deacetylase 4 (HDAC4) is a transcriptional regulator that has been implicated in a number of neurodevelopmental and neurodegenerative diseases that are associated with intellectual disability, cognitive defects, and/or memory loss. Both the accumulation of nuclear HDAC4 and its loss-of-function have been linked to these conditions, therefore exploring HDAC4’s role in neuronal function is essential to understand the molecular mechanisms underlying these diseases. In Drosophila, overexpression of HDAC4 results in defects in morphogenesis of axons in the mushroom body, a structure essential for memory formation, as well as long-term memory defects and disruption to the development of the compound eye. The molecular mechanisms underlying these HDAC4-induced phenotypes are currently unknown. RNA-sequencing on fly heads in which HDAC4 was overexpressed has previously been performed and showed few genes were transcriptionally regulated by HDAC4. In addition, an enhancer/suppressor rough eye phenotype screen has also been performed which identified a number of genes that interact genetically in the same molecular pathway as HDAC4. To further investigate the molecular mechanisms underlying HDAC4 dysfunction, an RNA interference (RNAi) based candidate screen for potential HDAC4-interactors was performed, which involved quantification of developmental defects in the mushroom body and eye following RNAi knockdown of each candidate. It was hypothesised that if a phenotype resulting from RNAi knockdown was similar to that induced by HDAC4 overexpression, that candidate may function in similar molecular pathways. A single candidate-interactor was selected (CG5846, named Peep) for further investigation. On overexpression, Peep and HDAC4 co- distribute in nuclei of mushroom body neurons, however no physical interaction was detected. Furthermore, overexpression of Peep did not rescue the HDAC4-induced mushroom body or eye defects. Due to the uncharacterised nature of Peep, a thorough investigation was performed to assess the importance of Peep in survival, longevity, motor function, brain development, courtship learning and memory, and wing development. Peep was observed to be essential for survival of glial cells and for normal mushroom body development, which warrants further investigation. Reduced expression of Peep also resulted in a unique severe necrotic eye phenotype, and through this, Peep was shown to play a potential role in processes involved in regulating mitochondrial and proteasomal function, apoptosis and oxidative stress. These data provide the first documented characterisation of the functional role of Peep in Drosophila development and provide the basis for further investigation into the underlying molecular mechanisms involved in mushroom body and eye development.
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/71269
dc.publisherMassey University
dc.publisherFigures are reproduced with permission.en
dc.rightsThe Author
dc.subjectHistone deacetylase
dc.subjectDrosophila melanogaster
dc.subjectMolecular genetics
dc.subjectNervous system
dc.subjectDiseases
dc.subjectGenetic aspects
dc.subjectPeep
dc.subjectHDAC4
dc.subjectdevelopment
dc.subjecteye
dc.subjectbrain
dc.subject.anzsrc310104 Cell neurochemistry
dc.titleCharacterising CG5846 (Peep) in Drosophila melanogaster neural function : a thesis presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Manawatū, New Zealand
thesis.degree.disciplineBiochemistry
thesis.degree.nameDoctor of Philosophy (Ph.D)
thesis.description.doctoral-citation-abridgedIn Drosophila melanogaster, the uncharacterised protein, CG5846, named Peep, is expressed in the brain. Miss Wilson undertook an investigation to determine the molecular roles of Peep in brain function. She determined that Peep is essential in the development of the eye and brain and in survival of brain cells. These results demonstrated the first characterisation of Peep.
thesis.description.doctoral-citation-longIn Drosophila melanogaster, the humble fruit fly, the uncharacterised protein, CG5846, named Peep, is expressed in the brain. Miss Wilson undertook an investigation to determine the molecular roles of Peep in brain function. She determined that Peep is essential in the development of the eye and brain and in survival of brain cells, where it plays a critical role in both neurons and glia. These results demonstrated the first characterisation of the functional role of Peep in development.
thesis.description.name-pronounciationSA-RAH JEAN WIL-SON
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