Recent genetic approaches have demonstrated that genetic factors contribute to the pathologic origins of neuropsychiatric disorders. Nevertheless, the exact pathophysiological mechanism for most cases remains unclear. Recent studies have demonstrated alterations in pathways of protein homeostasis (proteostasis) and identified several proteins that are misfolded and/or aggregated in the brains of patients with neuropsychiatric disorders, thus providing early evidence that disrupted proteostasis may be a contributing factor to their pathophysiology. Unlike neurodegenerative disorders in which massive neuronal and synaptic losses are observed, proteostasis impairments in neuropsychiatric disorders do not lead to robust neuronal death, but rather likely act via loss- and gain-of-function effects to disrupt neuronal and synaptic functions. Furthermore, abnormal activation of or overwhelmed endoplasmic reticulum and mitochondrial quality control pathways may exacerbate the pathophysiological changes initiated by impaired proteostasis, as these organelles are critical for proper neuronal functions and involved in the maintenance of proteostasis. This perspective article reviews recent findings implicating proteostasis impairments in the pathophysiology of neuropsychiatric disorders and explores how neuronal and synaptic functions may be impacted by disruptions in protein homeostasis. A greater understanding of the contributions by proteostasis impairment in neuropsychiatric disorders will help guide future studies to identify additional candidate proteins and new targets for therapeutic development.

最近的遗传方法表明，遗传因素有助于神经精神疾病的病理起源。然而，大多数病例的确切病理生理机制仍不清楚。最近的研究表明蛋白质稳态（蛋白质稳态）途径发生了改变，并确定了几种错误折叠和/或聚集在神经精神疾病患者大脑中的蛋白质，从而提供了早期证据表明蛋白质稳态破坏可能是其病理生理学的一个促成因素。与观察到大量神经元和突触损失的神经退行性疾病不同，神经精神疾病中的蛋白质稳态损伤不会导致强烈的神经元死亡，而是可能通过功能丧失和获得效应破坏神经元和突触功能。此外，内质网和线粒体质量控制通路的异常激活或不堪重负可能会加剧蛋白质稳态受损引发的病理生理变化，因为这些细胞器对于正常的神经元功能至关重要，并参与蛋白质稳态的维持。这篇观点文章回顾了最近的发现，这些发现涉及神经精神疾病病理生理学中的蛋白质稳态损伤，并探讨了蛋白质稳态破坏如何影响神经元和突触功能。更好地了解蛋白质稳态损伤在神经精神疾病中的作用将有助于指导未来的研究，以确定其他候选蛋白质和治疗开发的新靶点。