Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-synuclein inclusions
Proteasome mediates dopaminergic neuronal degeneration, and its inhibition causes α-synuclein inclusions
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DOI：
10.1074/jbc.m308434200
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发表时间：
2004-03-12
影响因子：
4.8
通讯作者：
Shimohama, S
中科院分区：
文献类型：
--
作者：
Sawada, H;Kohno, R;Shimohama, S
帕金森病的特点是多巴胺能神经元死亡和路易小体的存在。突触核蛋白是路易小体的主要成分，但其积累过程及其与多巴胺能神经元死亡的关系尚不清楚。虽然发病机制尚未明确，但线粒体复合体I受到抑制，caspase-3在受影响的中脑中被激活。在这里，我们报道了1-甲基-4-苯基吡啶离子（MPP+）或鱼烯酮和蛋白酶体抑制的结合导致α -突触核蛋白阳性包涵体的出现。然而，出乎意料的是，蛋白酶体抑制可阻断MPP+-或鱼藤酮诱导的多巴胺能神经元死亡。MPP+蛋白酶体活性升高，丝裂原活化蛋白激酶（MAPK）去磷酸化，caspase-3活化。蛋白酶体抑制逆转了MAPK去磷酸化，阻断了caspase-3的激活；神经保护作用被p42和p44 MAPK激酶抑制剂阻断。因此，蛋白酶体在包涵体形成和多巴胺能神经元死亡中都起着重要作用，但在该模型中，这些过程在蛋白酶体调节中是相反的。
Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. alpha-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death has not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed, and caspase-3 is activated in the affected midbrain. Here we report that a combination of 1-methyl-4-phenylpyridinium ion (MPP+) or rotenone and proteasome inhibition causes the appearance of alpha-synuclein-positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP+- or rotenone-induced dopaminergic neuronal death. MPP+ elevated proteasome activity, dephosphorylated mitogen-activating protein kinase ( MAPK), and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p42 and p44 MAPK kinase inhibitor. Thus, the proteasome plays an important role in both inclusion body formation and dopaminergic neuronal death but these processes form opposite sides on the proteasome regulation in this model.