Enokido Yasushi, Yoshitake Ayaka, Ito Hikaru, Okazawa Hitoshi
Department of Neuropathology, Medical Research Institute and 21st Century Center of Excellence Program (COE) for Brain Integration and Its Disorders, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
Biochem Biophys Res Commun. 2008 Nov 7;376(1):128-33. doi: 10.1016/j.bbrc.2008.08.108. Epub 2008 Aug 30.
HMGB1 is an evolutionarily conserved non-histone chromatin-associated protein with key roles in maintenance of nuclear homeostasis; however, the function of HMGB1 in the brain remains largely unknown. Recently, we found that the reduction of nuclear HMGB1 protein level in the nucleus associates with DNA double-strand break (DDSB)-mediated neuronal damage in Huntington's disease [M.L. Qi, K. Tagawa, Y. Enokido, N. Yoshimura, Y. Wada, K. Watase, S. Ishiura, I. Kanazawa, J. Botas, M. Saitoe, E.E. Wanker, H. Okazawa, Proteome analysis of soluble nuclear proteins reveals that HMGB1/2 suppress genotoxic stress in polyglutamine diseases, Nat. Cell Biol. 9 (2007) 402-414]. In this study, we analyze the region- and cell type-specific changes of HMGB1 and DDSB accumulation during the aging of mouse brain. HMGB1 is localized in the nuclei of neurons and astrocytes, and the protein level changes in various brain regions age-dependently. HMGB1 reduces in neurons, whereas it increases in astrocytes during aging. In contrast, DDSB remarkably accumulates in neurons, but it does not change significantly in astrocytes during aging. These results indicate that HMGB1 expression during aging is differentially regulated between neurons and astrocytes, and suggest that the reduction of nuclear HMGB1 might be causative for DDSB in neurons of the aged brain.
高迁移率族蛋白B1（HMGB1）是一种在进化上保守的非组蛋白染色质相关蛋白，在维持核稳态中起关键作用；然而，HMGB1在大脑中的功能仍 largely未知。最近，我们发现细胞核中HMGB1蛋白水平的降低与亨廷顿病中DNA双链断裂（DDSB）介导的神经元损伤相关[M.L.齐、K.田川、Y.榎户、N.吉村、Y.和田、K.渡濑、S.石浦、I.金泽、J.博塔斯、M.齐藤、E.E.万克、H.冈泽，可溶性核蛋白的蛋白质组分析表明HMGB1/2在多聚谷氨酰胺疾病中抑制基因毒性应激，《自然·细胞生物学》9（2007）402 - 414]。在本研究中，我们分析了小鼠大脑衰老过程中HMGB1和DDSB积累的区域和细胞类型特异性变化。HMGB1定位于神经元和星形胶质细胞的细胞核中，并且其蛋白水平在不同脑区随年龄而变化。衰老过程中，HMGB1在神经元中减少，而在星形胶质细胞中增加。相反，DDSB在神经元中显著积累，但在衰老过程中星形胶质细胞中无明显变化。这些结果表明衰老过程中HMGB1的表达在神经元和星形胶质细胞之间受到不同调节，并提示核HMGB1的减少可能是老年大脑神经元中DDSB的原因。
