Waddington John L, Zhen Xuechu, O'Tuathaigh Colm M P
School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland.
Jiangsu Key Laboratory of Translational Research & Therapy for Neuro-Psychiatric Disorders and Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, China.
Front Pharmacol. 2020 Jan 29;10:1638. doi: 10.3389/fphar.2019.01638. eCollection 2019.
Alongside positive and negative symptomatology, deficits in working memory, attention, selective learning processes, and executive function have been widely documented in schizophrenia spectrum psychosis. These cognitive abnormalities are strongly associated with impairment across multiple function domains and are generally treatment-resistant. The DTNBP1 (dystrobrevin-binding protein-1) gene, encoding dysbindin, is considered a risk factor for schizophrenia and is associated with variation in cognitive function in both clinical and nonclinical samples. Downregulation of DTNBP1 expression in dorsolateral prefrontal cortex and hippocampal formation of patients with schizophrenia has been suggested to serve as a primary pathophysiological process. Described as a "hub," dysbindin is an important regulatory protein that is linked with multiple complexes in the brain and is involved in a wide variety of functions implicated in neurodevelopment and neuroplasticity. The expression pattern of the various dysbindin isoforms (-1A, -1B, -1C) changes depending upon stage of brain development, tissue areas and subcellular localizations, and can involve interaction with different protein partners. We review evidence describing how sequence variation in DTNBP1 isoforms has been differentially associated with schizophrenia-associated symptoms. We discuss results linking these isoform proteins, and their interacting molecular partners, with cognitive dysfunction in schizophrenia, including evidence from drosophila through to genetic mouse models of dysbindin function. Finally, we discuss preclinical evidence investigating the antipsychotic potential of molecules that influence dysbindin expression and functionality. These studies, and other recent work that has extended this approach to other developmental regulators, may facilitate identification of novel molecular pathways leading to improved antipsychotic treatments.
除了阳性和阴性症状外，精神分裂症谱系精神病患者在工作记忆、注意力、选择性学习过程和执行功能方面的缺陷也有大量记录。这些认知异常与多个功能领域的损害密切相关，并且通常对治疗有抗性。编码联结蛋白的DTNBP1（肌营养不良蛋白结合蛋白-1）基因被认为是精神分裂症的一个风险因素，并且与临床和非临床样本中的认知功能变化有关。有研究表明，精神分裂症患者背外侧前额叶皮质和海马结构中DTNBP1表达的下调是一个主要的病理生理过程。联结蛋白被描述为一个“枢纽”，是一种重要的调节蛋白，与大脑中的多个复合物相关联，并参与了神经发育和神经可塑性的多种功能。各种联结蛋白异构体（-1A、-1B、-1C）的表达模式会根据大脑发育阶段、组织区域和亚细胞定位而变化，并且可能涉及与不同蛋白质伴侣的相互作用。我们综述了关于DTNBP1异构体序列变异如何与精神分裂症相关症状存在差异关联的证据。我们讨论了将这些异构体蛋白及其相互作用的分子伴侣与精神分裂症认知功能障碍联系起来的研究结果，包括从果蝇到联结蛋白功能的基因小鼠模型的证据。最后，我们讨论了研究影响联结蛋白表达和功能的分子的抗精神病潜力的临床前证据。这些研究以及最近将这种方法扩展到其他发育调节因子上的其他工作，可能有助于识别导致改进抗精神病治疗的新分子途径。
