Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin
Autism candidate gene DIP2A regulates spine morphogenesis via acetylation of cortactin
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自闭症候选基因 DIP2A 通过 cortactin 乙酰化调节脊柱形态发生。
DOI：
10.1371/journal.pbio.3000461
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发表时间：
2019-10-01
期刊：
影响因子：
9.8
通讯作者：
Zhu, Xiao-Juan
中科院分区：
文献类型：
--
作者：
Ma, Jun;Zhang, Lu-Qing;Zhu, Xiao-Juan
树突棘的发育对于兴奋性突触连接和功能性神经回路的建立至关重要。脊柱形态和密度的改变与多种神经系统疾病有关。孤独症候选基因断开相互作用蛋白同源物2A（DIP 2A）已知参与乙酰化辅酶A（Ac-CoA）的合成，并且主要在具有丰富的锥体神经元的脑区域中表达。然而，DIP 2A在大脑中的作用在很大程度上仍然未知。在本研究中，我们发现Dip 2a基因的缺失导致小鼠脊髓形态发生沿着出现缺陷，突触后致密物（PSD）变薄，锥体神经元的突触传递减少。我们进一步鉴定了DIP 2A与coronin相互作用，coronin是一种活性依赖性脊柱重塑蛋白。DIP 2A-PXXP基序（P，脯氨酸; X，任何残基）与皮质素-Src同源3（SH 3）结构域的结合活性对于维持乙酰化皮质素的水平至关重要。此外，Dip 2a基因敲除（KO）小鼠表现出自闭症样行为，包括过度重复行为和社交新奇性缺陷。重要的是，乙酰化模拟coronin恢复受损的突触传递和改善这些小鼠的重复行为。总之，我们的研究结果建立了自闭症谱系障碍（ASD）中DIP 2A基因变异之间的初步联系，并强调了突触蛋白乙酰化对突触加工的贡献。
Dendritic spine development is crucial for the establishment of excitatory synaptic connectivity and functional neural circuits. Alterations in spine morphology and density have been associated with multiple neurological disorders. Autism candidate gene disconnected-interacting protein homolog 2 A (DIP2A) is known to be involved in acetylated coenzyme A (Ac-CoA) synthesis and is primarily expressed in the brain regions with abundant pyramidal neurons. However, the role of DIP2A in the brain remains largely unknown. In this study, we found that deletion of Dip2a in mice induced defects in spine morphogenesis along with thin postsynaptic density (PSD), and reduced synaptic transmission of pyramidal neurons. We further identified that DIP2A interacted with cortactin, an activity-dependent spine remodeling protein. The binding activity of DIP2A-PXXP motifs (P, proline; X, any residue) with the cortactin-Src homology 3 (SH3) domain was critical for maintaining the level of acetylated cortactin. Furthermore, Dip2a knockout (KO) mice exhibited autism-like behaviors, including excessive repetitive behaviors and defects in social novelty. Importantly, acetylation mimetic cortactin restored the impaired synaptic transmission and ameliorated repetitive behaviors in these mice. Altogether, our findings establish an initial link between DIP2A gene variations in autism spectrum disorder (ASD) and highlight the contribution of synaptic protein acetylation to synaptic processing.