Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway.
Autism as early neurodevelopmental disorder: evidence for an sAPPα-mediated anabolic pathway.
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DOI：
10.3389/fncel.2013.00094
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发表时间：
2013
影响因子：
5.3
通讯作者：
Maloney B
中科院分区：
文献类型：
--
作者：
Lahiri DK;Sokol DK;Erickson C;Ray B;Ho CY;Maloney B
自闭症是一种神经发育障碍，其特征是社交技能和沟通缺陷以及干扰性重复行为。智力残疾往往伴随着自闭症。除了行为缺陷，自闭症的特征是神经病理学和大脑过度生长。颅内体积的增加往往伴随着这种大脑的生长。我们发现阿尔茨海默病（AD）相关的淀粉样β前体蛋白（APP），特别是其神经保护性加工产物分泌的APP α，在自闭症患者中升高。这导致了自闭症病因学的“合成代谢假说”，其中大脑中的神经元过度生长导致神经元间的错误连接，这可能是多种自闭症症状的基础。我们回顾了在脑容量和APP的合成代谢假说的研究的贡献，并与APP的其他蛋白质和途径，已经直接与自闭症，如脆性X智力低下蛋白，Ras小GT3/细胞外信号调节激酶，磷酸肌醇3激酶/蛋白激酶B/哺乳动物雷帕霉素的目标。我们还提出了额外的证据磁共振成像颅内测量有利于合成代谢假说。最后，由于APP参与自闭症似乎是多伙伴网络的一部分，我们将这一概念扩展到表观遗传学固有的互动领域。我们推测，影响APP对自闭症的贡献的潜在分子异常是由于环境影响而覆盖在潜在脆弱基因序列上的表观遗传标记。
Autism is a neurodevelopmental disorder marked by social skills and communication deficits and interfering repetitive behavior. Intellectual disability often accompanies autism. In addition to behavioral deficits, autism is characterized by neuropathology and brain overgrowth. Increased intracranial volume often accompanies this brain growth. We have found that the Alzheimer’s disease (AD) associated amyloid-β precursor protein (APP), especially its neuroprotective processing product, secreted APP α, is elevated in persons with autism. This has led to the “anabolic hypothesis” of autism etiology, in which neuronal overgrowth in the brain results in interneuronal misconnections that may underlie multiple autism symptoms. We review the contribution of research in brain volume and of APP to the anabolic hypothesis, and relate APP to other proteins and pathways that have already been directly associated with autism, such as fragile X mental retardation protein, Ras small GTPase/extracellular signal-regulated kinase, and phosphoinositide 3 kinase/protein kinase B/mammalian target of rapamycin. We also present additional evidence of magnetic resonance imaging intracranial measurements in favor of the anabolic hypothesis. Finally, since it appears that APP’s involvement in autism is part of a multi-partner network, we extend this concept into the inherently interactive realm of epigenetics. We speculate that the underlying molecular abnormalities that influence APP’s contribution to autism are epigenetic markers overlaid onto potentially vulnerable gene sequences due to environmental influence.
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