The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury.
The endogenous proteoglycan-degrading enzyme ADAMTS-4 promotes functional recovery after spinal cord injury.
复制标题
DOI：
10.1186/1742-2094-9-53
复制
发表时间：
2012-03-15
影响因子：
9.3
通讯作者：
Kadomatsu K
中科院分区：
文献类型：
--
作者：
Tauchi R;Imagama S;Natori T;Ohgomori T;Muramoto A;Shinjo R;Matsuyama Y;Ishiguro N;Kadomatsu K
在生理和病理条件下，硫酸软骨素蛋白多糖都是神经可塑性的主要抑制分子。硫酸软骨素降解酶软骨素酶ABC可促进成年啮齿动物脊髓损伤后的功能恢复，恢复经验依赖性可塑性，如眼优势可塑性和恐惧消除可塑性。这些数据表明，蛋白多糖部分中的糖链对于蛋白多糖的抑制活性是必不可少的。然而，核心蛋白的意义还没有得到广泛的研究。此外，考虑到软骨素酶ABC来源于细菌，一种哺乳动物内源性酶可以灭活蛋白多糖的活性，因此值得临床使用。测定了ADAMTS-4对硫酸软骨素蛋白多糖的核心蛋白，即短链蛋白聚糖、神经聚糖和磷酸多糖的降解活性。为了评价ADMATS-4活性的生物学意义，采用了体外轴突生长实验和体内神经元损伤模型-脊髓挫伤。ADAMTS-4可消化蛋白多糖，并逆转其对轴突生长的抑制作用。局部应用ADAMTS-4可显著促进脊髓损伤后运动功能的恢复。支持这些发现的是，ADAMTS-4治疗的脊髓在脊髓损伤后表现出增强的轴突再生/萌发。我们的数据表明，蛋白多糖部分中的核心蛋白对于抑制神经可塑性也是重要的，并为神经元损伤的治疗提供了一种潜在的更安全的工具。
Chondroitin sulfate proteoglycans are major inhibitory molecules for neural plasticity under both physiological and pathological conditions. The chondroitin sulfate degrading enzyme chondroitinase ABC promotes functional recovery after spinal cord injury, and restores experience-dependent plasticity, such as ocular dominance plasticity and fear erasure plasticity, in adult rodents. These data suggest that the sugar chain in a proteoglycan moiety is essential for the inhibitory activity of proteoglycans. However, the significance of the core protein has not been studied extensively. Furthermore, considering that chondroitinase ABC is derived from bacteria, a mammalian endogenous enzyme which can inactivate the proteoglycans' activity is desirable for clinical use. The degradation activity of ADAMTS-4 was estimated for the core proteins of chondroitin sulfate proteoglycans, that is, brevican, neurocan and phosphacan. To evaluate the biological significance of ADMATS-4 activity, an in vitro neurite growth assay and an in vivo neuronal injury model, spinal cord contusion injury, were employed. ADAMTS-4 digested proteoglycans, and reversed their inhibition of neurite outgrowth. Local administration of ADAMTS-4 significantly promoted motor function recovery after spinal cord injury. Supporting these findings, the ADAMTS-4-treated spinal cord exhibited enhanced axonal regeneration/sprouting after spinal cord injury. Our data suggest that the core protein in a proteoglycan moiety is also important for the inhibition of neural plasticity, and provides a potentially safer tool for the treatment of neuronal injuries.
登录
查看更多内容
DOI：
10.1083/jcb.127.6.1703
发表时间：
1994-12
期刊：
The Journal of cell biology
影响因子：
--
作者：
Milev P;Friedlander DR;Sakurai T;Karthikeyan L;Flad M;Margolis RK;Grumet M;Margolis RU
通讯作者：
Margolis RU
影响因子：
5.3
作者：
Jones, LL;Margolis, RU;Tuszynski, MH
通讯作者：
Tuszynski, MH
影响因子：
16.2
作者：
Kim, JE;Liu, BP;Strittmatter, SM
通讯作者：
Strittmatter, SM
影响因子：
5.3
作者：
Ito, Zenya;Sakamoto, Kazuma;Kadomatsu, Kenji
通讯作者：
Kadomatsu, Kenji
影响因子：
16.2
作者：
Neumann, S;Woolf, CJ
通讯作者：
Woolf, CJ