There are no validated biomarkers for schizophrenia (SCZ), a disorder linked to neural network dysfunction. We demonstrate that collapsin response mediator protein-2 (CRMP2), a master regulator of cytoskeleton and, hence, neural circuitry, may form the basis for a biomarker because its activity is uniquely imbalanced in SCZ patients. CRMP2’s activity depends upon its phosphorylation state. While an equilibrium between inactive (phosphorylated) and active (nonphosphorylated) CRMP2 is present in unaffected individuals, we show that SCZ patients are characterized by excess active CRMP2. We examined CRMP2 levels first in postmortem brains (correlated with neuronal morphometrics) and then, because CRMP2 is expressed in lymphocytes as well, in the peripheral blood of SCZ patients versus age-matched unaffected controls. In the brains and, more starkly, in the lymphocytes of SCZ patients <40 y old, we observed that nonphosphorylated CRMP2 was higher than in controls, while phosphorylated CRMP2 remained unchanged from control. In the brain, these changes were associated with dendritic structural abnormalities. The abundance of active CRMP2 with insufficient opposing inactive p-CRMP2 yielded a unique lowering of the p-CRMP2:CRMP2 ratio in SCZ patients, implying a disruption in the normal equilibrium between active and inactive CRMP2. These clinical data suggest that measuring CRMP2 and p-CRMP2 in peripheral blood might reflect intracerebral processes and suggest a rapid, minimally invasive, sensitive, and specific adjunctive diagnostic aid for early SCZ: increased CRMP2 or a decreased p-CRMP2:CRMP2 ratio may help cinch the diagnosis in a newly presenting young patient suspected of SCZ (versus such mimics as mania in bipolar disorder, where the ratio is high).

精神分裂症 (SCZ) 没有经过验证的生物标志物，这是一种与神经网络功能障碍有关的疾病。我们证明了折叠蛋白反应介质蛋白 2 (CRMP2)，细胞骨架的主要调节因子，因此，神经回路，可能构成生物标志物的基础，因为它的活性在 SCZ 患者中是独特的不平衡的。CRMP2 的活性取决于其磷酸化状态。虽然未受影响的个体中存在非活性（磷酸化）和活性（非磷酸化）CRMP2 之间的平衡，但我们表明 SCZ 患者的特征是活性 CRMP2 过多。我们首先检查了死后大脑中的 CRMP2 水平（与神经元形态计量学相关），然后由于 CRMP2 也在淋巴细胞中表达，因此在 SCZ 患者与年龄匹配的未受影响对照的外周血中。在大脑中，更明显的是，在 <40 岁的 SCZ 患者的淋巴细胞中，我们观察到非磷酸化的 CRMP2 高于对照，而磷酸化的 CRMP2 与对照保持不变。在大脑中，这些变化与树突结构异常有关。大量的活性 CRMP2 与相对的非活性 p-CRMP2 不足导致 SCZ 患者 p-CRMP2:CRMP2 比率的独特降低，这意味着活性和非活性 CRMP2 之间的正常平衡被破坏。这些临床数据表明，测量外周血中的 CRMP2 和 p-CRMP2 可能反映脑内过程，并建议对早期 SCZ 进行快速、微创、敏感和特异性的辅助诊断：CRMP2 增加或 p-CRMP2 减少：