Neurosignalling Group, Garvan Institute of Medical Research, Sydney, Australia.
FEBS J. 2013 Nov;280(21):5213-27. doi: 10.1111/febs.12407. Epub 2013 Jul 15.
The dominant genetic and environmental causes of mood disorders and schizophrenia have not been forthcoming, so alternative approaches are required to elucidate the mechanisms underlying these diseases and to develop improved treatments for use in the clinic. Pharmacological evidence implicates glycogen synthase kinase 3 (GSK3) as a key target of current therapeutics, and this is well supported by genetic studies in animal models. Several upstream regulators of GSK3 are also genetically associated with mood disorders and schizophrenia, further suggesting convergence on GSK3 signalling. Whereas pathways upstream of GSK3 are being elucidated, relatively little progress has been made in identifying targets downstream of GSK3 that mediate its functional effects. This is important, because these substrates themselves could become next-generation therapeutic targets that are more potent and specific than current therapeutics targeting GSK3. Here, a few likely candidates and their connection to mood disorders and schizophrenia are discussed.
心境障碍和精神分裂症的主要遗传和环境病因尚未明确，因此需要采用其他方法来阐明这些疾病的发病机制，并开发用于临床的改良治疗方法。药理学证据表明糖原合酶激酶 3（GSK3）是当前治疗药物的关键靶点，动物模型的遗传研究也很好地支持了这一点。GSK3 的几个上游调节剂也与心境障碍和精神分裂症存在遗传关联，这进一步提示 GSK3 信号通路的汇聚。虽然 GSK3 的上游途径正在被阐明，但在确定介导其功能效应的 GSK3 下游靶标方面相对进展甚微。这很重要，因为这些底物本身可能成为下一代治疗靶点，其比当前针对 GSK3 的治疗药物更有效和更具特异性。在这里，讨论了一些可能的候选物及其与心境障碍和精神分裂症的关系。
