Investigating HDAC4 aggregation in a Drosophila model of neuronal development : a dissertation 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.authorHawley, Hannah Rose
dc.date.accessioned2024-07-01T02:49:24Z
dc.date.available2024-07-01T02:49:24Z
dc.date.issued2024-06-21
dc.description.abstractHistone deacetylase four (HDAC4) is essential in neuronal development and function, and dysregulation of HDAC4 has been observed in a number of neurodevelopmental and neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. In particular, its aberrant nuclear accumulation is a common feature among these diseases, and it has been observed that upon upregulation or accumulation in the nucleus, HDAC4 forms punctate foci in neuronal nuclei. Previous research in a Drosophila model determined that overexpression of HDAC4 disrupted both neuronal development and long-term memory, and this was largely mediated by the nuclear pool of HDAC4. Based on these data, it was hypothesised that aggregates of HDAC4 are responsible for the neurotoxicity that leads to disrupted neurodevelopment and memory. Therefore, this study aimed to determine whether the presence of HDAC4 nuclear aggregates correlated with neurodevelopmental deficits in a Drosophila model of neurodevelopment, and if so, how they mediate their toxic effects. The N-terminus of HDAC4 forms homo-oligomers in solution, and it was hypothesised that full-length HDAC4 similarly oligomerises, and that this is required for its aggregation in neuronal nuclei. Mutations predicted to prevent oligomerisation were introduced into the N- terminus of HDAC4 and were shown to significantly reduce aggregation of HDAC4 in Drosophila neurons. Furthermore, their presence also reduced the severity of HDAC4 overexpression-induced impairments in neurodevelopment. Conversely, stabilisation of oligomerisation increased aggregation and the severity of neurodevelopmental phenotypes, together indicating that aggregation positively correlates with the severity of neurodevelopmental deficits. HDAC4 aggregates have been previously shown to sequester the transcription factor MEF2, and further investigation revealed that the presence of MEF2 stabilised aggregation and increased the severity of defects in neuronal development. Importantly, targeting the interaction between HDAC4 and MEF2 reduced the severity of these defects. Other than MEF2, the composition of HDAC4 aggregates is unknown, and therefore immunoprecipitation-coupled mass spectrometry was performed on nuclear HDAC4 to identify candidate interactors of aggregates. This revealed a number of proteins with roles in neuronal development and function, as well as those involved in splicing and protein homeostasis, suggesting that aggregates may be impairing these processes to mediate toxicity. Together these data indicate that nuclear aggregation of HDAC4 impairs neurodevelopment, and may constitute a novel biomarker of disease or therapeutic target. Given the overlap in aetiology between neurodevelopmental and neurodegenerative diseases, further investigation of whether HDAC4 aggregation contributes to the severity and/or progression of neurodegenerative disorders is warranted.
dc.identifier.urihttps://mro.massey.ac.nz/handle/10179/70051
dc.publisherMassey Universityen
dc.publisherListed in 2024 Dean's List of Exceptional Thesesen
dc.rightsThe Authoren
dc.subjectDrosophila melanogasteren
dc.subjectNervous systemen
dc.subjectDiseasesen
dc.subjectGenetic aspectsen
dc.subjectCell aggregationen
dc.subjectHistone deacetylaseen
dc.subjectHDAC4
dc.subjectMEF2
dc.subjectneurodevelopment
dc.subjectprotein aggregation
dc.subjectbrain
dc.subjectneuron
dc.subjectphotoreceptor
dc.subjectmushroom body
dc.subjecteye
dc.subjectDean's List of Exceptional Thesesen
dc.subject.anzsrc310104 Cell neurochemistryen
dc.titleInvestigating HDAC4 aggregation in a Drosophila model of neuronal development : a dissertation presented in partial fulfilment of the requirements for the degree of Doctor of Philosophy in Biochemistry at Massey University, Manawatū, New Zealanden
thesis.degree.disciplineBiochemistry
thesis.degree.nameDoctor of Philosophy (Ph.D.)
thesis.description.doctoral-citation-abridgedMiss Hawley investigated the nuclear aggregation of histone deacetylase four, which has been observed to occur in brains of patients with neurodevelopmental and neurodegenerative disease. She found that this aggregation leads to impaired neuronal development and function, and identified new avenues for development of drugs that may reduce the severity of neuronal disease.
thesis.description.doctoral-citation-longHistone deacetylase four (HDAC4) is an essential protein in neuronal development and function, and often accumulates in nuclei in brains of patients with neurodevelopmental and neurodegenerative diseases. Previous research in a Drosophila model showed increased nuclear HDAC4 impaired neuronal development and long-term memory, and it was hypothesised that nuclear aggregates of HDAC4 were responsible for this. Miss Hawley investigated how HDAC4 forms aggregates, and demonstrated a positive correlation between aggregation and neurotoxicity in Drosophila. These data have identified further avenues that are of interest for drug development to reduce the severity of neuronal disease.
thesis.description.name-pronounciationHannah Rose Hawley HAN NAH ROSE HORE LEE
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