Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy
Progranulin overexpression in sensory neurons attenuates neuropathic pain in mice: Role of autophagy
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DOI：
10.1016/j.nbd.2016.09.010
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发表时间：
2016-12-01
影响因子：
6.1
通讯作者：
Tegeder, Irmgard
中科院分区：
文献类型：
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作者：
Altmann, Christine;Hardt, Stefanie;Tegeder, Irmgard
外周或中枢神经损伤是慢性疼痛的常见原因，其机制尚未完全了解。使用新产生的转基因小鼠，我们表明，在感觉神经元颗粒蛋白前体过表达减轻坐骨神经损伤后的神经病理性疼痛，并加速神经愈合。酵母双杂交筛选揭示了颗粒蛋白前体与自噬相关蛋白ATG 12和ATG 4 b的假定相互作用。这得到了共定位和蛋白质组学研究的支持，这些研究显示了ATG 13和ATG 4 b以及自噬网络的其他成员、溶酶体蛋白和参与内吞作用的蛋白质的调节。在初级感觉神经元中证实了颗粒蛋白前体与自噬通路的关联。自噬和生存受损的progranulin缺陷的神经元和改善progranulin过度表达的神经元。在体内神经损伤引起的积累LC 3b-EGFP阳性小体的背根神经节和神经的神经元，表明损伤的自噬通量。这些神经元中颗粒蛋白前体的过表达与应激标志物ATF 3的减少、受损神经中蛋白质聚集物的减少和残端愈合的增强有关。在行为水平上，羟氯喹进一步抑制自噬流增强了坐骨神经损伤后的冷和热伤害感受，抵消了颗粒蛋白前体提供的疼痛保护作用。我们推断，颗粒蛋白前体可能有助于清除蛋白质废物，从而有助于解决神经损伤后的神经病理性疼痛。(C)2016 Elsevier Inc. All rights reserved.
Peripheral or central nerve injury is a frequent cause of chronic pain and the mechanisms are not fully understood. Using newly generated transgenic mice we show that progranulin overexpression in sensory neurons attenuates neuropathic pain after sciatic nerve injury and accelerates nerve healing. A yeast-2-hybrid screen revealed putative interactions of progranulin with autophagy-related proteins, ATG12 and ATG4b. This was supported by colocalization and proteomic studies showing regulations of ATG13 and ATG4b and other members of the autophagy network, lysosomal proteins and proteins involved in endocytosis. The association of progranulin with the autophagic pathway was functionally confirmed in primary sensory neurons. Autophagy and survival were impaired in progranulin-deficient neurons and improved in progranulin overexpressing neurons. Nerve injury in vivo caused an accumulation of LC3b-EGFP positive bodies in neurons of the dorsal root ganglia and nerves suggesting an impairment of autophagic flux. Overexpression of progranulin in these neurons was associated with a reduction of the stress marker ATF3, fewer protein aggregates in the injured nerve and enhanced stump healing. At the behavioral level, further inhibition of the autophagic flux by hydroxychloroquine intensified cold and heat nociception after sciatic nerve injury and offset the pain protection provided by progranulin. We infer that progranulin may assist in removal of protein waste and thereby helps to resolve neuropathic pain after nerve injury. (C) 2016 Elsevier Inc. All rights reserved.