Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder
Positive effect of exogenous brain-derived neurotrophic factor on impaired neurite development and mitochondrial function in dopaminergic neurons derived from dental pulp stem cells from children with attention deficit hyperactivity disorder
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DOI：
10.1016/j.bbrc.2019.04.084
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发表时间：
2019-06-11
影响因子：
3.1
通讯作者：
Masuda, Keiji
中科院分区：
文献类型：
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作者：
Huong Thi Nguyen Nguyen;Kato, Hiroki;Masuda, Keiji
注意缺陷多动障碍（ADHD）是最常见的神经发育障碍之一，其特征是注意力受损、多动和冲动。虽然 ADHD 涉及多种病因，但其潜在机制仍不清楚。尽管之前的研究表明多巴胺能信号、线粒体和脑源性神经营养因子（BDNF）在 ADHD 中存在失调，但很少有研究直接报道这些关联。来自人类脱落乳牙 (SHED) 的干细胞可以有效分化为多巴胺能神经元 (DN)，因此是研究与 DN 功能障碍相关的神经发育障碍的有用的疾病特异性细胞模型。本研究旨在通过分析从三名 ADHD 男孩的 SHED 中分化而来的 DN，并将其与三名正常发育男孩的 DN 进行比较，旨在阐明 ADHD 中 DN、线粒体和 BDNF 之间的关系。在细胞培养基中缺乏外源性 BDNF 的情况下，源自 ADHD 男孩的 DN (ADHD-DN) 表现出神经突生长和分支受损、神经突中线粒体质量减少以及细胞内 ATP 水平异常。此外，ADHD-DN 中 BDNF mRNA 显着减少。然而，补充 BDNF 可以显着改善 ADHD-DN 的神经突发育和线粒体功能。这些结果表明，ADHD-DN 可能会损害与 BDNF 生成不足相关的神经突发育和线粒体功能，而补充外源性 BDNF 可能会改善这种情况。来自患者的 SHED 的这些发现可能有助于未来针对与 ADHD 发病机制有关的异常多巴胺能信号、线粒体功能和 BDNF 水平的治疗策略的开发。 (C) 2019 Elsevier Inc. 保留所有权利。
Attention deficit hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders and is characterized by impaired attention, hyperactivity, and impulsivity. While multiple etiologies are implicated in ADHD, its underlying mechanism(s) remain unclear. Although previous studies have suggested dysregulation of dopaminergic signals, mitochondria, and brain-derived neurotrophic factor (BDNF) in ADHD, few studies have reported these associations directly. Stem cells from human exfoliated deciduous teeth (SHED) can efficiently differentiate into dopaminergic neurons (DNs) and are thus a useful disease-specific cellular model for the study of neurodevelopmental disorders associated with DN dysfunction. This study aimed to elucidate the relationships between DNs, mitochondria, and BDNF in ADHD by analyzing DNs differentiated from SHED obtained from three boys with ADHD and comparing them to those from three typically developing boys. In the absence of exogenous BDNF in the cell culture media, DNs derived from boys with ADHD (ADHD-DNs) exhibited impaired neurite outgrowth and branching, decreased mitochondrial mass in neurites, and abnormal intracellular ATP levels. In addition, BDNF mRNA was significantly decreased in ADHD-DNs. Supplementation with BDNF, however, significantly improved neurite development and mitochondrial function in ADHD-DNs. These results suggest that ADHD-DNs may have impaired neurite development and mitochondrial function associated with insufficient production of BDNF, which may be improved by exogenous BDNF supplementation. Findings such as these, from patient-derived SHED, may contribute to the future development of treatment strategies for aberrant dopaminergic signaling, mitochondrial functioning, and BDNF levels implicated in ADHD pathogenesis. (C) 2019 Elsevier Inc. All rights reserved.