Increased Abundance of Nuclear HDAC4 Impairs Neuronal Development and Long-Term Memory

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dc.citation.volume14
dc.contributor.authorFitzsimons H
dc.contributor.authorMain P
dc.contributor.authorWheeler D
dc.contributor.authorTan WJ
dc.date.available2021-03-30
dc.date.available2021-03-09
dc.date.issued30/03/2021
dc.description.abstractDysregulation of the histone deacetylase HDAC4 is associated with both neurodevelopmental and neurodegenerative disorders, and a feature common to many of these disorders is impaired cognitive function. HDAC4 shuttles between the nucleus and cytoplasm in both vertebrates and invertebrates and alterations in the amounts of nuclear and/or cytoplasmic HDAC4 have been implicated in these diseases. In Drosophila, HDAC4 also plays a critical role in the regulation of memory, however, the mechanisms through which it acts are unknown. Nuclear and cytoplasmically-restricted HDAC4 mutants were expressed in the Drosophila brain to investigate a mechanistic link between HDAC4 subcellular distribution, transcriptional changes and neuronal dysfunction. Deficits in mushroom body morphogenesis, eye development and long-term memory correlated with increased abundance of nuclear HDAC4 but were associated with minimal transcriptional changes. Although HDAC4 sequesters MEF2 into punctate foci within neuronal nuclei, no alteration in MEF2 activity was observed on overexpression of HDAC4, and knockdown of MEF2 had no impact on long-term memory, indicating that HDAC4 is likely not acting through MEF2. In support of this, mutation of the MEF2 binding site within HDAC4 also had no impact on nuclear HDAC4-induced impairments in long-term memory or eye development. In contrast, the defects in mushroom body morphogenesis were ameliorated by mutation of the MEF2 binding site, as well as by co-expression of MEF2 RNAi, thus nuclear HDAC4 acts through MEF2 to disrupt mushroom body development. These data provide insight into the mechanisms through which dysregulation of HDAC4 subcellular distribution impairs neurological function and provides new avenues for further investigation.
dc.description.publication-statusPublished
dc.identifierhttp://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000639421500001&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=c5bb3b2499afac691c2e3c1a83ef6fef
dc.identifierARTN 616642
dc.identifier.citationFRONTIERS IN MOLECULAR NEUROSCIENCE, 2021, 14
dc.identifier.doi10.3389/fnmol.2021.616642
dc.identifier.elements-id442398
dc.identifier.harvestedMassey_Dark
dc.identifier.issn1662-5099
dc.identifier.urihttps://hdl.handle.net/10179/16254
dc.publisherFrontiers Media
dc.relation.isPartOfFRONTIERS IN MOLECULAR NEUROSCIENCE
dc.relation.urihttps://doi.org/10.3389/fnmol.2021.616642
dc.subjectHDAC4
dc.subjecthistone deacetylase
dc.subjectmemory
dc.subjectneuron
dc.subjectAlzheimer
dc.subjectDrosophila
dc.subjectMEF2
dc.subject.anzsrc1103 Clinical Sciences
dc.subject.anzsrc1109 Neurosciences
dc.titleIncreased Abundance of Nuclear HDAC4 Impairs Neuronal Development and Long-Term Memory
dc.typeJournal article
pubs.notesNot known
pubs.organisational-group/Massey University
pubs.organisational-group/Massey University/College of Sciences
pubs.organisational-group/Massey University/College of Sciences/School of Natural Sciences
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