Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder
Implication of Endoplasmic Reticulum Stress in Autism Spectrum Disorder
复制标题
DOI：
10.1007/s11064-017-2370-1
复制
发表时间：
2018-01-01
影响因子：
4.4
通讯作者：
Mimori, Seisuke
中科院分区：
文献类型：
--
作者：
Kawada, Koichi;Mimori, Seisuke
根据《疾病诊断和统计手册》第五版，自闭症谱系障碍（ASD）被归类为神经发育障碍，并被定义为中枢神经系统的先天性损伤。 ASD 可能是由染色体异常或基因突变引起的。然而，这些病因不足以解释 ASD 的发病机制。因此，我们提出ASD的病因和发病机制与内质网（ER）应激有关。在自闭症谱系障碍 (ASD) 小鼠模型中，由丙戊酸诱导的内质网应激增加，其特征是这种应激激活的未折叠蛋白反应。在 ASD 中观察到神经突生长和突触因子表达的抑制。同样，内质网应激会抑制神经突的生长和突触因子的表达。此外，自闭症谱系障碍患者中还观察到大脑增生。内质网应激还可以增强神经元分化。突触因子，如细胞粘附分子和柄，在神经回路的形成中发挥重要作用。因此，内质网应激与神经元分化、神经突生长和突触蛋白表达的异常相关。内质网应激会提高泛素蛋白连接酶 HRD1 的表达，从而降解未折叠蛋白。自闭症谱系障碍 (ASD) 患者死后，中额叶皮质中的 HRD1 表达显着增加。此外，HRD1 沉默改善了 ER 应激引起的异常。由于其他泛素连接酶与神经突生长有关，因此内质网应激可能通过神经元分化或成熟异常与神经元发育疾病的发病机制有关。
Autism spectrum disorder (ASD) is categorized as a neurodevelopmental disorder according to the Diagnostic and Statistical Manual of Disorders, Fifth Edition and is defined as a congenital impairment of the central nervous system. ASD may be caused by a chromosomal abnormality or gene mutation. However, these etiologies are insufficient to account for the pathogenesis of ASD. Therefore, we propose that the etiology and pathogenesis of ASD are related to the stress of the endoplasmic reticulum (ER). ER stress, induced by valproic acid, increased in ASD mouse model, characterized by an unfolded protein response that is activated by this stress. The inhibition of neurite outgrowth and expression of synaptic factors are observed in ASD. Similarly, ER stress suppresses the neurite outgrowth and expression of synaptic factors. Additionally, hyperplasia of the brain is observed in patients with ASD. ER stress also enhances neuronal differentiation. Synaptic factors, such as cell adhesion molecule and shank, play important roles in the formation of neural circuits. Thus, ER stress is associated with the abnormalities of neuronal differentiation, neurite outgrowth, and synaptic protein expression. ER stress elevates the expression of the ubiquitin-protein ligase HRD1 for the degradation of unfolded proteins. HRD1 expression significantly increased in the middle frontal cortex in the postmortem of patients with ASD. Moreover, HRD1 silencing improved the abnormalities induced by ER stress. Because other ubiquitin ligases are related with neurite outgrowth, ER stress may be related to the pathogenesis of neuronal developmental diseases via abnormalities of neuronal differentiation or maturation.