Anti-CV2 autoantibodies unmask a CRMP5/GluN2B pain signaling hub

摘要 神经病理性疼痛是一种常见的神经系统疾病，影响到5%-10%的普通人群和 由于人口老龄化，预计未来将变得更加常见。尽管止痛药是 这种类型的疼痛对我们目前的治疗策略尤其具有抵抗力，使患者几乎没有 选择。此外，这些药物还会产生严重的副作用。当然，这对个人来说是非常虚弱的， 对他们的生活质量产生负面影响。此外，它还具有重大的经济影响(治疗成本， 花费在工作之外的时间)，并且是需要解决的医疗服务的负担。因此，有一个 迫切需要开发新的更有针对性的疗法来治疗神经病理性疼痛。一个障碍是 缺乏从基础科学成果到临床的转化。在这里，我们的目标是通过使用 患者样本增强了我们基础研究的相关性。现在人们普遍认为，神经免疫 相互作用有助于异常疼痛状态，而IS的一个相对研究较少的方面是通过动作 人类自身抗体。抗CV2自身抗体针对的是一种名为崩溃蛋白反应介体的蛋白质 蛋白5(CRMP5)，与患者的神经病理性疼痛有关。CRMP5是一种未被充分研究的肿瘤 在发育中的大脑中高度表达的蛋白质。在成年人中，CRMP5在大脑中不表达，但 保留在感觉神经元中，神经和突触存在于脊髓中。在神经病理性疼痛中，CRMP5 脊髓突触后部位的表达减少，而GluN2B的水平，一个亚单位的 NMDA受体和一种新的CRMP5结合蛋白增加。使用患者自身抗体和一只大鼠 神经病理性疼痛模型，我们将检验CRMP5功能障碍是痛觉异常的基础的假设。 抗CV2自身免疫性神经病和神经病理性疼痛。目标1将研究感觉的变化 抗CV2自身抗体诱导的神经传递。这将包括感觉神经元的功能描述。 采用全细胞和切片电生理学。据此，我们将破译抗CV2的作用部位。 自身抗体会导致痛觉过敏。目标2将重点阐明CRMP5的突触前和突触后功能 脊髓神经传递和神经病理性疼痛。我们将探索失去CRMP5调控的新想法 GluN2B的表达是神经病理性疼痛中痛觉异常的基础。这一建议使用了新的生物化学和 CRMP5(抗-CV2)自身免疫所致临床表现的功能翻译 询问CRMP5如何导致神经病理性疼痛。一种新型治疗药物的鉴定 针对慢性疼痛的目标是一个令人兴奋的结果，对未来的治疗开发具有深远的应用价值。

Abstract Neuropathic pain is common neurological disorder affecting between 5-10% of the general population and predicted to become more common in the future because of the aging population. Although analgesics are available, this type of pain is particularly resistant to our current treatment strategies leaving patients with few options. In addition, these drugs cause severe side effects. This is of course hugely debilitating for individuals, negatively affecting their quality of life. Furthermore, it has significant economic ramifications (treatment costs, time spent off work) and is a burden on healthcare services that needs to be addressed. As a result, there is a pressing need to develop new better-targeted therapies for the treatment of neuropathic pain. One obstacle has been the lack of translation from basic science findings into the clinic. Here, we aim to address this by using patient samples to enhance the relevance of our basic research. It is now well accepted that neuroimmune interactions contribute to abnormal pain states and one relatively under studied aspect of is through the action of human autoantibodies. The anti-CV2 autoantibodies target a protein called collapsin response mediator protein 5 (CRMP5) and are associated with neuropathic pain in patients. CRMP5 is an understudied onconeural protein highly expressed in the developing brain. In adults, CRMP5 expression is absent from the brain but retained in sensory neurons, nerves and synapses present in the spinal cord. In neuropathic pain, CRMP5 expression is decreased at post-synaptic sites in the spinal cord, while the levels of GluN2B, a subunit of the NMDA receptor, and a novel CRMP5 binding protein, is increased. Using patients' autoantibodies and a rat model of neuropathic pain, we will test the hypothesis that disruption of CRMP5 functions underlies allodynia in anti-CV2 autoimmune neuropathy and in neuropathic pain. Aim 1 will investigate the alterations of sensory neurotransmission elicited by anti-CV2 autoantibodies. This will include a functional profiling of sensory neurons using whole cell and slice electrophysiology. With this we will decipher the site of action of anti-CV2 autoantibodies produce to allodynia. Aim 2 will focus on elucidating the pre- and post-synaptic function of CRMP5 in spinal neurotransmission and neuropathic pain. We will explore the novel idea that loss of CRMP5 regulation of GluN2B underlies allodynia in neuropathic pain. This proposal uses a combination of novel biochemical and functional methods to reverse-translate the clinical findings of CRMP5 (anti-CV2) auto-immunity causing allodynia to interrogate how CRMP5 can contribute to neuropathic pain. The identification of a novel therapeutic target for chronic pain is an exciting outcome with far reaching applications for future therapeutic development.