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

Patrick Main,Helen L Fitzsimons,David Wheeler,Wei Jun Tan

doi:10.3389/fnmol.2021.616642

Patrick Main, Helen L Fitzsimons + Show 2 more

Open Access

https://doi.org/10.3389/fnmol.2021.616642

Copy DOI

Abstract

Dysregulation 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.

Highlights

Dysregulation of the histone deacetylase HDAC4 results in impairments in neuronal development and formation of long-term memories in the Drosophila brain (Fitzsimons et al, 2013)
We investigated whether nuclear HDAC4 was responsible for the long-term memory deficits we have previously observed on overexpression of DmHDAC4 in the adult mushroom body (Fitzsimons et al, 2013)
We previously showed that HDAC4 interacts genetically with the SUMOylation machinery and that the SUMO E3 ligase Ubc9 is required for long-term memory (LTM) in Drosophila, but increased nuclear HDAC4 did not appear to alter global SUMOylation, nor facilitate SUMOylation of candidates MEF2, CREB, CaMKII or itself

Summary

Introduction

Dysregulation of the histone deacetylase HDAC4 results in impairments in neuronal development and formation of long-term memories in the Drosophila brain (Fitzsimons et al, 2013). A frameshift mutation that results in nuclear accumulation of HDAC4 results in features consistent with 2q37 deletion syndrome (Williams et al, 2010) and expression of the corresponding mouse variant of HDAC4 in the mouse brain causes deficits in spatial learning and memory (Sando et al, 2012). This may be initially surprising given that this mutant lacks a deacetylase domain, HDAC4 is catalytically inactive in vertebrates and there are no global changes in histone acetylation resulting from knockout of HDAC4 in mice (Mielcarek et al, 2013b). Nuclear accumulation of HDAC4 has been observed in human Alzheimer’s disease post-mortem brains as well as the brains of Alzheimer’s mice with the abundance of nuclear HDAC4 correlating with increased clinical dementia scores in humans (Herrup et al, 2013; Shen et al, 2016), indicating that excess abundance of nuclear HDAC4 impairs cognitive function

Objectives

Methods

Results

Conclusion