Thomsen Maj Schneider, Andersen Michelle Vandborg, Christoffersen Pia Rægaard, Jensen Malene Duedal, Lichota Jacek, Moos Torben
Laboratory for Neurobiology, Biomedicine Group, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Laboratory for Neurobiology, Biomedicine Group, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
Neurobiol Dis. 2015 Sep;81:108-18. doi: 10.1016/j.nbd.2015.03.013. Epub 2015 Mar 20.
Chronic inflammation in the substantia nigra (SN) accompanies conditions with progressive neurodegeneration. This inflammatory process contributes to gradual iron deposition that may catalyze formation of free-radical mediated damage, hence exacerbating the neurodegeneration. This study examined proteins related to iron-storage (ferritin) and iron-export (ferroportin) (aka metal transporter protein 1, MTP1) in a model of neurodegeneration. Ibotenic acid injected stereotactically into the striatum leads to loss of GABAergic neurons projecting to SN pars reticulata (SNpr), which subsequently leads to excitotoxicity in the SNpr as neurons here become vulnerable to their additional glutamatergic projections from the subthalamic nucleus. This imbalance between glutamate and GABA eventually led to progressive shrinkage of the SNpr and neuronal loss. Neuronal cell death was accompanied by chronic inflammation as revealed by the presence of cells expressing ED1 and CD11b in the SNpr and the adjacent white matter mainly denoted by the crus cerebri. The SNpr also exhibited changes in iron metabolism seen as a marked accumulation of inflammatory cells containing ferric iron and ferritin with morphology corresponding to macrophages and microglia. Ferritin was detected in neurons of the lesioned SNpr in contrast to the non-injected side. Compared to non-injected rats, surviving neurons of the SNpr expressed ferroportin at unchanged level. Analyses of dissected SNpr using RT-qPCR showed a rise in ferritin-H and -L transcripts with increasing age but no change was observed in the lesioned side compared to the non-lesioned side, indicating that the increased expression of ferritin in the lesioned side occurred at the post-transcriptional level. Hepcidin transcripts were higher in the lesioned side in contrast to ferroportin mRNA that remained unaltered. The continuous entry of iron-containing inflammatory cells into the degenerating SNpr and their subsequent demise is probably responsible for iron donation in neurodegeneration. This is accompanied by only a slight increase in neuronal ferritin and not ferroportin, which suggests that the iron-containing debris of dying inflammatory cells and degenerating neurons gets scavenged by invading macrophages and activated microglia to prevent an increase in neuronal iron.
黑质（SN）中的慢性炎症伴随着进行性神经退行性变的病症。这种炎症过程导致逐渐的铁沉积，可能催化自由基介导的损伤形成，从而加剧神经退行性变。本研究在神经退行性变模型中检测了与铁储存（铁蛋白）和铁输出（铁转运蛋白）（又称金属转运蛋白1，MTP1）相关的蛋白质。立体定向注射到纹状体中的鹅膏蕈氨酸导致投射到黑质网状部（SNpr）的γ-氨基丁酸能神经元丧失，随后导致SNpr中的兴奋性毒性，因为这里的神经元变得易受来自丘脑底核的额外谷氨酸能投射的影响。谷氨酸和γ-氨基丁酸之间的这种失衡最终导致SNpr逐渐萎缩和神经元丧失。如在SNpr和主要由大脑脚表示的相邻白质中存在表达ED1和CD11b的细胞所揭示的，神经元细胞死亡伴随着慢性炎症。SNpr还表现出铁代谢的变化，表现为含有三价铁和铁蛋白的炎性细胞显著积聚，其形态与巨噬细胞和小胶质细胞相对应。与未注射侧相比，在受损SNpr的神经元中检测到铁蛋白。与未注射的大鼠相比，SNpr存活的神经元中铁转运蛋白表达水平未改变。使用RT-qPCR对解剖的SNpr进行分析显示，随着年龄增长，铁蛋白-H和-L转录本增加，但与未受损侧相比，受损侧未观察到变化，表明受损侧铁蛋白表达增加发生在转录后水平。与保持不变的铁转运蛋白mRNA相比，受损侧的铁调素转录本更高。含铁血炎性细胞持续进入退化的SNpr及其随后的死亡可能是神经退行性变中铁捐赠的原因。这仅伴随着神经元铁蛋白的轻微增加，而不是铁转运蛋白，这表明死亡炎性细胞和退化神经元的含铁碎片被侵入的巨噬细胞和活化的小胶质细胞清除，以防止神经元铁增加。
