Main Patrick, Tan Wei Jun, Wheeler David, Fitzsimons Helen L
Biochemistry, Biotechnology and Biomedical Science Group, School of Fundamental Sciences, Massey University, Palmerston North, New Zealand.
NSW Department of Primary Industries, Orange, NSW, Australia.
Front Mol Neurosci. 2021 Mar 30;14:616642. doi: 10.3389/fnmol.2021.616642. eCollection 2021.
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 , 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 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 , and knockdown of 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 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.
组蛋白去乙酰化酶HDAC4的失调与神经发育障碍和神经退行性疾病都有关联，而这些疾病许多共有的一个特征是认知功能受损。在脊椎动物和无脊椎动物中，HDAC4在细胞核和细胞质之间穿梭，细胞核和/或细胞质中HDAC4含量的改变与这些疾病有关。此外，HDAC4在记忆调节中也起着关键作用，然而，其作用机制尚不清楚。在果蝇大脑中表达了细胞核和细胞质受限的HDAC4突变体，以研究HDAC4亚细胞分布、转录变化和神经元功能障碍之间的机制联系。蘑菇体形态发生、眼睛发育和长期记忆的缺陷与细胞核HDAC4丰度增加相关，但转录变化最小。尽管HDAC4将MEF2隔离到神经元细胞核内的点状病灶中，但在过表达时未观察到MEF2活性的改变，并且敲低MEF2对长期记忆没有影响，这表明HDAC4可能不是通过MEF2起作用。支持这一点的是，HDAC4内MEF2结合位点的突变对细胞核HDAC4诱导的长期记忆或眼睛发育损伤也没有影响。相反，MEF2结合位点的突变以及RNAi的共表达改善了蘑菇体形态发生的缺陷，因此细胞核HDAC4通过MEF2起作用来破坏蘑菇体发育。这些数据为HDAC4亚细胞分布失调损害神经功能的机制提供了见解，并为进一步研究提供了新的途径。
