据美国每日科学网报道，伦敦国王学院的彼得·吉斯领导的研究小组近日找到了影响精神分裂症的分子途径，并使用一种常用的抗癌药物MS-275成功地缓解了小鼠的精神分裂症症状。这项研究为研发精神分裂药物提供了新途径。论文发表在期刊《脑》（Brain）上。
精神分裂症会导致幻觉、妄想和行为改变等长期心理症状，全球约2400万人受其影响，未经治疗的精神分裂患者有90%居于发展中国家。虽然人们普遍认为这是遗传和环境的共同作用，但其确切缘由尚未被知晓。目前精神分裂症的治疗方法，包括心理治疗如心理疗法、咨询、认知行为治疗和药物治疗，但很多抗精神病药物和绝大多数的安定药都有极大副作用。
吉斯团队在研究中首次发现，精神分裂症患者脑内的酶催化剂p35变少。正常的大脑发育部分是由Cdk5蛋白质的活化作用所保证的，而Cdk5的激活需要大脑中酶p35的存在，但精神分裂症患者大脑中酶p35比正常人少50%。
他们将小鼠的酶p35的含量减少到了相应的比例，然后对小鼠脑内的分子变化进行了监控。结果发现，p35的减少导致小鼠体内对维持神经连接有重要作用的突触蛋白质减少，并显露出神经分裂相关症状，如学习障碍、对感官刺激无法作出回应，表现出认知功能障碍等。
研究还发现，p35的减少引起的分子变化与抗癌药物MS-275的药物靶点相一致。MS-275不仅处理了小鼠的分子变化，而且减少了其与精神分裂症相关的症状。了解这一信号通路及p35减少所引起的后果，对精神分裂症潜在的治疗方法有重要指导作用。
吉斯称，该研究成果鼓舞了未来治疗精神分裂症患者的药物研发，有助于精神分裂症的治疗。(生物谷 Bioon.com)
doi:10.1093/brain/awr155
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Schizophrenia is associated with dysregulation of a Cdk5 activator that regulates synaptic protein expression and cognition
Olivia Engmann, Tibor Hortobágyi, Ruth Pidsley, Claire Troakes, Hans-Gert Bernstein, Michael R. Kreutz, Jonathan Mill, Margareta Nikolic and Karl Peter Giese
Cyclin-dependent kinase 5 is activated by small subunits, of which p35 is the most abundant. The functions of cyclin-dependent kinase 5 signalling in cognition and cognitive disorders remains unclear. Here, we show that in schizophrenia, a disorder associated with impaired cognition, p35 expression is reduced in relevant brain regions. Additionally, the expression of septin 7 and OPA1, proteins downstream of truncated p35, is decreased in schizophrenia. Mimicking a reduction of p35 in heterozygous knockout mice is associated with cognitive endophenotypes. Furthermore, a reduction of p35 in mice results in protein changes similar to schizophrenia post-mortem brain. Hence, heterozygous p35 knockout mice model both cognitive endophenotypes and molecular changes reminiscent of schizophrenia. These changes correlate with reduced acetylation of the histone deacetylase 1 target site H3K18 in mice. This site has previously been shown to be affected by truncated p35. By restoring H3K18 acetylation with the clinically used specific histone deacetylase 1 inhibitor MS-275 both cognitive and molecular endophenotypes of schizophrenia can be rescued in p35 heterozygous knockout mice. In summary, we suggest that reduced p35 expression in schizophrenia has an impact on synaptic protein expression and cognition and that these deficits can be rescued, at least in part, by the inhibition of histone deacetylase 1.
