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Mitochondria Under the Spotlight: On the Implications of Mitochondrial Dysfunction and its Connectivity to Neuropsychiatric Disorders
Computational and Structural Biotechnology Journal ( IF 4.4 ) Pub Date : 2020-09-14 , DOI: 10.1016/j.csbj.2020.09.008
Mara Zilocchi , Kirsten Broderick , Sadhna Phanse , Khaled A. Aly , Mohan Babu

Neuropsychiatric disorders (NPDs) such as bipolar disorder (BD), schizophrenia (SZ) and mood disorder (MD) are hard to manage due to overlapping symptoms and lack of biomarkers. Risk alleles of BD/SZ/MD are emerging, with evidence suggesting mitochondrial (mt) dysfunction as a critical factor for disease onset and progression. Mood stabilizing treatments for these disorders are scarce, revealing the need for biomarker discovery and artificial intelligence approaches to design synthetically accessible novel therapeutics. Here, we show mt involvement in NPDs by associating 245 mt proteins to BD/SZ/MD, with 7 common players in these disease categories. Analysis of over 650 publications suggests that 245 NPD-linked mt proteins are associated with 800 other mt proteins, with mt impairment likely to rewire these interactions. High dosage of mood stabilizers is known to alleviate manic episodes, but which compounds target mt pathways is another gap in the field that we address through mood stabilizer-gene interaction analysis of 37 prescriptions and over-the-counter psychotropic treatments, which we have refined to 15 mood-stabilizing agents. We show 26 of the 245 NPD-linked mt proteins are uniquely or commonly targeted by one or more of these mood stabilizers. Further, induced pluripotent stem cell-derived patient neurons and three-dimensional human brain organoids as reliable BD/SZ/MD models are outlined, along with multiomics methods and machine learning-based decision making tools for biomarker discovery, which remains a bottleneck for precision psychiatry medicine.



中文翻译:

线粒体在聚光灯下:关于线粒体功能障碍的含义及其与神经精神疾病的联系

由于症状重叠和缺乏生物标志物,难以控制神经精神疾病(NPD),例如双相情感障碍(BD),精神分裂症(SZ)和情绪障碍(MD)。BD / SZ / MD的风险等位基因正在出现,证据表明线粒体(mt)功能障碍是疾病发作和进展的关键因素。这些疾病的情绪稳定治疗方法十分匮乏,这表明需要生物标记物发现和人工智能方法来设计可合成的新型治疗方法。在这里,我们通过将245 mt蛋白与BD / SZ / MD相关联,显示了mt在NPD中的参与,这些疾病类别中有7个常见参与者。对超过650种出版物的分析表明,与NPD连锁的245种mt蛋白与800种其他mt蛋白相关,而mt损伤可能会重新结合这些相互作用。众所周知,高剂量的情绪稳定剂可以缓解躁狂发作,但是靶向mt途径的化合物是我们在该领域的另一个空白,我们将通过对37种处方的情绪稳定剂-基因相互作用分析以及非处方的精神治疗来解决这一问题15种稳定情绪的药物。我们显示245个NPD连接的mt蛋白中有26个被一种或多种这些情绪稳定剂独特或普遍靶向。此外,概述了诱导多能干细胞来源的患者神经元和三维人脑类器官作为可靠的BD / SZ / MD模型,以及用于生物标记物发现的多组学方法和基于机器学习的决策工具,这仍然是精度的瓶颈精神医学。但通过mt途径靶向的化合物是该领域的另一个空白,我们将通过对37种处方和非处方精神疗法的情绪稳定剂-基因相互作用分析来解决这一问题,我们已将其精炼为15种情绪稳定剂。我们显示245个NPD连接的mt蛋白中有26个被一种或多种这些情绪稳定剂独特或普遍靶向。此外,概述了诱导多能干细胞来源的患者神经元和三维人脑类器官作为可靠的BD / SZ / MD模型,以及用于生物标志物发现的多组学方法和基于机器学习的决策工具,这仍然是精度的瓶颈精神医学。但通过mt途径靶向的化合物是该领域的另一个空白,我们将通过对37种处方和非处方精神疗法的情绪稳定剂-基因相互作用分析来解决这一问题,我们已将其精炼为15种情绪稳定剂。我们显示245个NPD连接的mt蛋白中有26个被一种或多种这些情绪稳定剂独特或普遍靶向。此外,概述了诱导多能干细胞来源的患者神经元和三维人脑类器官作为可靠的BD / SZ / MD模型,以及用于生物标记物发现的多组学方法和基于机器学习的决策工具,这仍然是精度的瓶颈精神医学。我们已将其精炼为15种稳定情绪的药物。我们显示245个NPD连接的mt蛋白中有26个被一种或多种这些情绪稳定剂独特或普遍靶向。此外,概述了诱导多能干细胞来源的患者神经元和三维人脑类器官作为可靠的BD / SZ / MD模型,以及用于生物标记物发现的多组学方法和基于机器学习的决策工具,这仍然是精度的瓶颈精神医学。我们已将其精炼为15种稳定情绪的药物。我们显示245个NPD连接的mt蛋白中有26个被一种或多种这些情绪稳定剂独特或普遍靶向。此外,概述了诱导多能干细胞来源的患者神经元和三维人脑类器官作为可靠的BD / SZ / MD模型,以及用于生物标记物发现的多组学方法和基于机器学习的决策工具,这仍然是精度的瓶颈精神医学。

更新日期:2020-09-14
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