Merenlender-Wagner Avia, Shemer Zeev, Touloumi Olga, Lagoudaki Roza, Giladi Eliezer, Andrieux Annie, Grigoriadis Nikolaos C, Gozes Illana
a The Adams Super Center for Brain Studies; The Lily and Avraham Gildor Chair for the Investigation of Growth Factors; The Elton Laboratory for Neuroendocrinology; Department of Human Molecular Genetics and Biochemistry; Sagol School of Neuroscience; Sackler Faculty of Medicine ; Tel Aviv University ; Tel Aviv ; Israel.
Autophagy. 2014;10(12):2324-32. doi: 10.4161/15548627.2014.984274.
Autophagy plays a key role in the pathophysiology of schizophrenia as manifested by a 40% decrease in BECN1/Beclin 1 mRNA in postmortem hippocampal tissues relative to controls. This decrease was coupled with the deregulation of the essential ADNP (activity-dependent neuroprotector homeobox), a binding partner of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β) another major constituent of autophagy. The drug candidate NAP (davunetide), a peptide fragment from ADNP, enhanced the ADNP-LC3B interaction. Parallel genetic studies have linked allelic variation in the gene encoding MAP6/STOP (microtubule-associated protein 6) to schizophrenia, along with altered MAP6/STOP protein expression in the schizophrenic brain and schizophrenic-like behaviors in Map6-deficient mice. In this study, for the first time, we reveal significant decreases in hippocampal Becn1 mRNA and reversal by NAP but not by the antipsychotic clozapine (CLZ) in Map6-deficient (Map6(+/-)) mice. Normalization of Becn1 expression by NAP was coupled with behavioral protection against hyperlocomotion and cognitive deficits measured in the object recognition test. CLZ reduced hyperlocomotion below control levels and did not significantly affect object recognition. The combination of CLZ and NAP resulted in normalized outcome behaviors. Phase II clinical studies have shown NAP-dependent augmentation of functional activities of daily living coupled with brain protection. The current studies provide a new mechanistic pathway and a novel avenue for drug development.
自噬在精神分裂症的病理生理学中起关键作用，表现为与对照组相比，死后海马组织中BECN1/Beclin 1 mRNA减少40%。这种减少与必需的ADNP（活性依赖性神经保护同源框）失调有关，ADNP是自噬的另一个主要成分MAP1LC3B/LC3B（微管相关蛋白1轻链3β）的结合伴侣。候选药物NAP（达武奈肽）是一种来自ADNP的肽片段，可增强ADNP-LC3B相互作用。平行的遗传学研究已将编码MAP6/STOP（微管相关蛋白6）的基因中的等位基因变异与精神分裂症联系起来，同时精神分裂症患者大脑中MAP6/STOP蛋白表达改变，Map6缺陷小鼠出现精神分裂症样行为。在本研究中，我们首次发现Map6缺陷（Map6(+/-)）小鼠海马Becn1 mRNA显著减少，NAP可使其逆转，但抗精神病药物氯氮平（CLZ）不能。NAP使Becn1表达正常化，同时在物体识别试验中对过度活动和认知缺陷具有行为保护作用。CLZ将过度活动降低至对照水平以下，对物体识别没有显著影响。CLZ和NAP联合使用可使行为结果正常化。II期临床研究表明，NAP可增强日常生活功能活动并具有脑保护作用。目前的研究提供了一条新机制途径和一个新的药物开发途径。
