Decreased activity of the 20S proteasome in the brain white matter and gray matter of patients with multiple sclerosis.
Decreased activity of the 20S proteasome in the brain white matter and gray matter of patients with multiple sclerosis.
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DOI：
10.1111/j.1471-4159.2011.07182.x
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发表时间：
2011-04
影响因子：
4.7
通讯作者：
Bizzozero OA
中科院分区：
文献类型：
--
作者：
Zheng J;Bizzozero OA
已知羰基化（氧化）蛋白质在多发性硬化（MS）患者的大脑白色物质（WM）和灰质（GM）中积累。虽然氧化应激是羰基生成所必需的，但降解系统的失效最终导致组织内羰基化蛋白质的积聚。在这项研究中，我们测量了20 S蛋白酶体和其他蛋白水解系统的活动，在大脑WM和GM的13名MS患者和13名对照。我们报告的20 S蛋白酶体的三个肽酶（即糜蛋白酶样，半胱天冬酶样和胰蛋白酶样）的活动在MS-WM和MS-GM大大降低。有趣的是，在这种疾病中，蛋白酶体的数量和催化亚基（β 1，β 2和β 5）的水平都没有减少。含有Lys-48聚泛素的蛋白质也在MS组织中积累，表明26S蛋白酶体也失效。MS中调节帽PA 28 α和PA 700的水平也低于对照组，表明更复杂的蛋白酶体的活性可能进一步降低。最后，其他蛋白酶（钙蛋白酶、组织蛋白酶B、线粒体LonP）的活性也可能去除氧化蛋白，但在MS中并未减弱。总之，这些研究表明，20 S颗粒中蛋白水解中心的直接失活和/或特异性抑制剂的存在是MS中蛋白酶体功能障碍的根本原因。
Carbonylated (oxidized) proteins are known to accumulate in the cerebral white matter (WM) and gray matter (GM) of patients with multiple sclerosis (MS). While oxidative stress is necessary for carbonyl generation, it is the failure of the degradation systems that ultimately leads to the build-up of carbonylated proteins within tissues. In this study, we measured the activity of the 20S proteasome and other proteolytic systems in the cerebral WM and GM of 13 MS patients and 13 controls. We report that the activities of the three peptidases of the 20S proteasome (i.e. chymotrypsin-like, caspase-like and trypsin-like) in both MS-WM and MS-GM are greatly reduced. Interestingly, neither the amount of proteasome nor the levels of the catalytic subunits (β1, β2, and β5) are diminished in this disease. Proteins containing Lys-48 poly-ubiquitin also accumulate in MS tissues, indicating failure of the 26S proteasome as well. Levels of the regulatory caps PA28α and PA700 are also lower in MS than in controls, suggesting that the activity of the more complex proteasomes may be reduced further. Finally, the activities of other proteases that might also remove oxidized proteins (calpain, cathepsin B, mitochondrial LonP) are not lessened in MS. Together, these studies suggest that direct inactivation of proteolytic centers in the 20S particle and/or the presence of specific inhibitors is the underlying cause of proteasomal dysfunction in MS.
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