Overexpressed Down Syndrome Cell Adhesion Molecule (DSCAM) Deregulates P21-Activated Kinase (PAK) Activity in an In Vitro Neuronal Model of Down Syndrome: Consequences on Cell Process Formation and Extension
Overexpressed Down Syndrome Cell Adhesion Molecule (DSCAM) Deregulates P21-Activated Kinase (PAK) Activity in an In Vitro Neuronal Model of Down Syndrome: Consequences on Cell Process Formation and Extension
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DOI：
10.1007/s12640-016-9613-9
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发表时间：
2016-07-01
影响因子：
3.7
通讯作者：
Caviedes, Pablo
中科院分区：
文献类型：
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作者：
Perez-Nunez, Ramon;Barraza, Natalia;Caviedes, Pablo
在人类中，唐氏综合症 (DS) 是由常染色体 21 的额外拷贝引起的。DS 患者最引人注目的发现是智力障碍和成年后出现类似阿尔茨海默病 (AD) 的神经病理学。基因过量最有可能导致 DS 中发育障碍以及神经元功能改变。最近，细胞信号传导和调节途径的破坏与 DS 病理生理学有关，许多此类途径可能代表不同 DS 相关基因的共同目标，而这些基因反过来又可能代表有吸引力的治疗目标。在这方面，一种DS相关基因唐氏综合症细胞粘附分子（DSCAM）在神经元增殖、成熟和突触发生中具有重要功能。 p21 相关激酶 (PAK) 似乎是最有趣的研究可能性，因为众所周知 DSCAM 可以调节 PAK 通路。因此，在 DS 中，过度表达的 DSCAM 可能会解除 PAK 活性的调节，并影响调节突触可塑性的信号通路，例如树突棘动力学和轴突引导和生长。在目前的工作中，我们使用源自DS动物模型（例如16三体（Ts16）胎鼠（命名为CTb））的大脑皮层的永生化细胞系，以及从正常同窝小鼠（命名为CNh）建立的类似细胞系，来研究DSCAM在PAKs途径中的作用。本研究表明，与 CNh 细胞相比，DSCAM 在 CTb 细胞中过度表达约两倍。一致地，在 CTb 细胞中 DSCAM 激活后，PAK1 及其下游效应器 LIMK 和 cofilin 保持磷酸化状态较长时间，导致肌动蛋白动力学改变，在三体条件下表现为基础 F/G 比率增加和神经突生长减少。目前的工作提出了 DSCAM 基因过度表达与 PAK 通路失调之间的相关性，导致三体细胞系中神经元可塑性的形态参数改变，即突起数量和长度减少。
In humans, Down syndrome (DS) is caused by the presence of an extra copy of autosome 21. The most striking finding in DS patients is intellectual disability and the onset of Alzheimer's disease (AD)-like neuropathology in adulthood. Gene overdose is most likely to underlie both developmental impairments, as well as altered neuronal function in DS. Lately, the disruption of cellular signaling and regulatory pathways has been implicated in DS pathophysiology, and many of such pathways may represent common targets for diverse DS-related genes, which could in turn represent attractive therapeutical targets. In this regard, one DS-related gene Down Syndrome Cell Adhesion Molecule (DSCAM), has important functions in neuronal proliferation, maturation, and synaptogenesis. p21-associated kinases (PAKs) appear as a most interesting possibility for study, as DSCAM is known to regulate the PAKs pathway. Hence, in DS, overexpressed DSCAM could deregulate PAKs activity and affect signaling pathways that regulate synaptic plasticity such as dendritic spine dynamics and axon guidance and growth. In the present work, we used an immortalized cell line derived from the cerebral cortex of an animal model of DS such as the trisomy 16 (Ts16) fetal mouse (named CTb), and a similar cell line established from a normal littermate (named CNh), to study the effect of DSCAM in the PAKs pathway. The present study shows that DSCAM is overexpressed in CTb cells by approximately twofold, compared to CNh cells. Congruently, PAK1, as well as its downstream effectors LIMK and cofilin, stay phosphorylated for longer periods after DSCAM activation in the CTb cells, leading to an altered actin dynamics, expressed as an increased basal F/G ratio and reduced neurite growth, in the trisomic condition. The present work presents the correlation between DSCAM gene overexpression and a dysregulation of the PAK pathway, resulting in altered morphological parameters of neuronal plasticity in the trisomic cell line, namely decreased number and length of processes.