Institute of Clinical Pharmacology, Goethe-University Hospital, Frankfurt, Germany.
Functional Proteomics, SFB815 Core Unit, Goethe-University, Frankfurt, Germany.
Biochim Biophys Acta Mol Basis Dis. 2017 Nov;1863(11):2727-2745. doi: 10.1016/j.bbadis.2017.07.014. Epub 2017 Jul 15.
Affective and cognitive processing of nociception contributes to the development of chronic pain and vice versa, pain may precipitate psychopathologic symptoms. We hypothesized a higher risk for the latter with immanent neurologic diseases and studied this potential interrelationship in progranulin-deficient mice, which are a model for frontotemporal dementia, a disease dominated by behavioral abnormalities in humans. Young naïve progranulin deficient mice behaved normal in tests of short-term memory, anxiety, depression and nociception, but after peripheral nerve injury, they showed attention-deficit and depression-like behavior, over-activity, loss of shelter-seeking, reduced impulse control and compulsive feeding behavior, which did not occur in equally injured controls. Hence, only the interaction of 'pain x progranulin deficiency' resulted in the complex phenotype at young age, but neither pain nor progranulin deficiency alone. A deep proteome analysis of the prefrontal cortex and olfactory bulb revealed progranulin-dependent alterations of proteins involved in synaptic transport, including neurotransmitter transporters of the solute carrier superfamily. In particular, progranulin deficiency was associated with a deficiency of nuclear and synaptic zinc transporters (ZnT9/Slc30a9; ZnT3/Slc30a3) with low plasma zinc. Dietary zinc supplementation partly normalized the attention deficit of progranulin-deficient mice, which was in part reminiscent of autism-like and compulsive behavior of synaptic zinc transporter Znt3-knockout mice. Hence, the molecular studies point to defective zinc transport possibly contributing to progranulin-deficiency-associated psychopathology. Translated to humans, our data suggest that neuropathic pain may precipitate cognitive and psychopathological symptoms of an inherent, still silent neurodegenerative disease.
伤害感受的情感和认知加工有助于慢性疼痛的发展，反之亦然，疼痛可能引发精神病理症状。我们假设内在神经疾病的后者风险更高，并在颗粒蛋白缺乏的小鼠中研究了这种潜在的相互关系，颗粒蛋白缺乏的小鼠是额颞叶痴呆的模型，这种疾病在人类中以行为异常为主。年轻的幼稚颗粒蛋白缺乏的小鼠在短期记忆、焦虑、抑郁和伤害感受测试中表现正常，但在外周神经损伤后，它们表现出注意力缺陷和类似抑郁的行为、过度活跃、失去寻求庇护、冲动控制减少和强迫进食行为，而同样受伤的对照组则没有出现这些行为。因此，只有“疼痛 x 颗粒蛋白缺乏”的相互作用导致了年轻小鼠的复杂表型，而不是单纯的疼痛或颗粒蛋白缺乏。对前额叶皮层和嗅球的深度蛋白质组分析显示，颗粒蛋白依赖性改变了参与突触转运的蛋白质，包括溶质载体超家族的神经递质转运体。特别是，颗粒蛋白缺乏与核和突触锌转运体（ZnT9/Slc30a9；ZnT3/Slc30a3）的缺乏有关，导致血浆锌水平降低。膳食锌补充部分纠正了颗粒蛋白缺乏小鼠的注意力缺陷，这在一定程度上让人联想到突触锌转运体 Znt3 敲除小鼠的自闭症样和强迫行为。因此，分子研究表明，锌转运缺陷可能导致颗粒蛋白缺乏相关的精神病理学。将这些数据转化为人类，我们的数据表明，神经病理性疼痛可能引发潜在的、仍处于沉默状态的神经退行性疾病的认知和精神病理症状。
