Rearranged during transfection (RET), in complex with glial cell line-derived (GDNF) family receptor alpha (GFRα), is the canonical signaling receptor for GDNF family ligands (GFLs) expressed in both central and peripheral parts of the nervous system and also in non-neuronal tissues. RET-dependent signaling elicited by GFLs has an important role in the development, maintenance and survival of dopamine and sensory neurons. Both Parkinson’s disease and neuropathic pain are devastating disorders without an available cure, and at the moment are only treated symptomatically. GFLs have been studied extensively in animal models of Parkinson’s disease and neuropathic pain with remarkable outcomes. However, clinical trials with recombinant or viral vector-encoded GFL proteins have produced inconclusive results. GFL proteins are not drug-like; they have poor pharmacokinetic properties and activate multiple receptors. Targeting RET and/or GFRα with small molecules may resolve the problems associated with using GFLs as drugs and can result in the development of therapeutics for disease-modifying treatments against Parkinson’s disease and neuropathic pain.

中文翻译：

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胶质细胞源性神经营养因子 (GFL) 和靶向 RET 受体的小分子用于治疗疼痛和帕金森病


转染过程中重排 (RET) 与神经胶质细胞系衍生 (GDNF) 家族受体 α (GFRα) 复合，是 GDNF 家族配体 (GFL) 的典型信号受体，在神经系统的中枢和外周部分表达，也是在非神经元组织中。 GFL 引发的 RET 依赖性信号传导在多巴胺和感觉神经元的发育、维持和存活中具有重要作用。帕金森病和神经性疼痛都是毁灭性的疾病，无法治愈，目前只能进行对症治疗。 GFL 已在帕金森病和神经性疼痛的动物模型中进行了广泛研究，并取得了显着的效果。然而，重组或病毒载体编码的 GFL 蛋白的临床试验尚未得出结论。 GFL 蛋白不是药物样的；它们的药代动力学特性较差并激活多个受体。用小分子靶向 RET 和/或 GFRα 可能会解决与使用 GFL 作为药物相关的问题，并可能导致针对帕金森病和神经性疼痛的疾病缓解疗法的开发。