Magaki Shino, Mueller Claudius, Yellon Steven M, Fox James, Kim Joseph, Snissarenko Eugene, Chin Vernon, Ghosh Manik C, Kirsch Wolff M
Neurosurgery Center for Research, Training and Education, Loma Linda University School of Medicine, Loma Linda, CA 92350, USA.
Brain Res. 2007 Jul 16;1158:144-50. doi: 10.1016/j.brainres.2007.05.004. Epub 2007 May 8.
Iron is a trace metal essential for normal brain development but toxic in excess as it is capable of generating highly reactive radicals that damage cells and tissue. Iron is stringently regulated by the iron regulatory proteins, IRP1 and IRP2, which regulate proteins involved in iron homeostasis at the posttranscriptional level. In this study, 12 distinct regions were microdissected from the mouse brain and regional changes in the levels of loosely bound and non-heme iron that occur with development were measured. We examined 6, 12, and 24 week old wildtype C57BL/6 mice and mice with a targeted deletion of iron regulatory protein 2 (IRP2-/-) that have been reported to develop neurodegenerative symptoms in adulthood. In wildtype mice, levels of loosely bound iron decreased while non-heme iron increased with development. In contrast, an increase in loosely bound and a more pronounced increase in non-heme iron was seen in IRP2-/- mice between 6 and 12 weeks of age, stemming from lower levels at 6 weeks (the youngest age examined) compared to wildtype. These results have implications for understanding the increase in regional brain iron that is associated with normal aging and is postulated to be exacerbated in neurodegenerative disorders.
铁是一种微量金属，对正常脑发育至关重要，但过量时具有毒性，因为它能够产生损害细胞和组织的高活性自由基。铁受到铁调节蛋白IRP1和IRP2的严格调控，这两种蛋白在转录后水平调节参与铁稳态的蛋白质。在本研究中，从小鼠大脑中显微切割出12个不同区域，并测量了发育过程中松散结合铁和非血红素铁水平的区域变化。我们研究了6周龄、12周龄和24周龄的野生型C57BL/6小鼠以及铁调节蛋白2靶向缺失的小鼠（IRP2-/-），据报道后者在成年后会出现神经退行性症状。在野生型小鼠中，松散结合铁的水平随着发育而降低，而非血红素铁的水平则升高。相比之下，在6至12周龄的IRP2-/-小鼠中，松散结合铁增加，非血红素铁增加更为明显，这是由于与野生型相比，6周龄（所检测的最小年龄）时水平较低。这些结果对于理解与正常衰老相关的区域脑铁增加以及推测在神经退行性疾病中会加剧的情况具有重要意义。
