Proteasome regulates dopaminergic neuronel degeneration and Lewy body formation

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。α-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。虽然发病机制尚不清楚，但在受影响的中脑，线粒体复合体I受到抑制，caspase-3被激活。在本研究项目中，我们证明了1-甲基-4-苯基吡啶离子（MPP^+）或鱼藤酮与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，蛋白酶体抑制抑制了MPP^+-或鱼藤酮诱导的多巴胺能神经元死亡。MPP^+提高26S蛋白酶体、去磷酸化丝裂原活化激酶（MAPK）和活化caspase-3的活性。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p-42和p-44 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形成相反的两个方面。

Parkinson's disease is characterized by dopaminergic neuronal death and the presence of Lewy bodies. α-Synuclein is a major component of Lewy bodies, but the process of its accumulation and its relationship to dopaminergic neuronal death have not been resolved. Although the pathogenesis has not been clarified, mitochondrial complex I is suppressed and caspase-3 is activated in the affected midbrain. In this research project, we demonstrated that a combination of 1-methyl-4-phenylpyridinium ion (MPP^+) or rotenone and proteasome inhibition caused the appearance of α-synuclein positive inclusion bodies. Unexpectedly, however, proteasome inhibition blocked MPP^+-or rotenone-induced dopaminergic neuronal death. MPP^+ elevated the activity of 26S proteasome, dephosphorylated mitogen activating kinase (MAPK) and activated caspase-3. Proteasome inhibition reversed the MAPK dephosphorylation and blocked caspase-3 activation; the neuroprotection was blocked by a p-42 and p-44 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.