Bjornson Kathryn J, Vanderplow Amanda M, Bhasker Aishwarya I, Cahill Michael E
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, WI 53706, USA.
Cell Rep Med. 2024 Jul 16;5(7):101652. doi: 10.1016/j.xcrm.2024.101652.
Based on recent genome-wide association studies, it is theorized that altered regulation of autophagy contributes to the pathophysiology of schizophrenia and bipolar disorder. As activity of autophagy-regulatory pathways is controlled by discrete phosphorylation sites on the relevant proteins, phospho-protein profiling is one of the few approaches available for enabling a quantitative assessment of autophagic activity in the brain. Despite this, a comprehensive phospho-protein assessment in the brains of schizophrenia and bipolar disorder subjects is currently lacking. Using this direction, our broad screening identifies an increase in AMP-activated protein kinase (AMPK)-mediated phospho-activation of the pro-autophagy protein beclin-1 solely in the prefrontal cortex of female, but not male, schizophrenia subjects. Using a reverse translational approach, we surprisingly find that this increase in beclin-1 activity facilitates synapse formation and enhances cognition. These findings are interpreted in the context of human studies demonstrating that female schizophrenia subjects have a lower susceptibility to cognitive dysfunction than males.
基于近期的全基因组关联研究，理论推测自噬调节的改变促成了精神分裂症和双相情感障碍的病理生理学过程。由于自噬调节通路的活性受相关蛋白上离散磷酸化位点的控制，磷酸化蛋白质谱分析是能够对大脑中自噬活性进行定量评估的少数可用方法之一。尽管如此，目前仍缺乏对精神分裂症和双相情感障碍患者大脑进行全面的磷酸化蛋白质评估。按照这个方向，我们的广泛筛查发现，仅在女性精神分裂症患者而非男性患者的前额叶皮质中，存在由AMP激活的蛋白激酶（AMPK）介导的自噬促进蛋白贝克林1的磷酸化激活增加的情况。通过反向转化方法，我们惊人地发现贝克林1活性的这种增加促进了突触形成并增强了认知能力。这些发现结合人类研究结果进行解读，表明女性精神分裂症患者比男性对认知功能障碍的易感性更低。
