Inhibition of proteasome activity sensitizes dopamine neurons to protein alterations and oxidative stress
Inhibition of proteasome activity sensitizes dopamine neurons to protein alterations and oxidative stress
复制标题
DOI：
10.1007/s00702-004-0167-2
复制
发表时间：
2004-10
影响因子：
3.3
通讯作者：
C. Mytilineou;K. McNaught;P. Shashidharan;Jocelyn A. Yabut;R. Baptiste;A. Parnandi;C. Olanow
中科院分区：
文献类型：
--
作者：
C. Mytilineou;K. McNaught;P. Shashidharan;Jocelyn A. Yabut;R. Baptiste;A. Parnandi;C. Olanow
泛素-蛋白酶体途径清除不需要蛋白质的能力受损与帕金森病（PD）中发生的细胞死亡有关。在PD患者的黑质中发现了蛋白酶体结构和功能的缺陷，以及蛋白质聚集和氧化蛋白水平的升高，支持了这一概念。我们之前已经证明，中脑培养物中蛋白酶体活性的抑制会诱导多巴胺能神经元的变性，并伴随蛋白胞内包涵体的形成。在本研究中，我们研究了在氧化应激和蛋白质错误折叠联合作用下，蛋白酶体抑制对培养多巴胺神经元的影响，以便更好地模拟PD的情况。我们证明了两种结构无关的蛋白酶体活性抑制剂，lactacystin和carbobenzoxy- l- leucl -l -leucyl- l- leucinal (MG132)，会导致剂量依赖性细胞损失，并优先影响多巴胺能神经元。促进蛋白质损伤和错误折叠的条件，如氧化应激、热休克和大麻碱，也会诱导神经元变性，多巴胺神经元优先丧失，当这些条件与蛋白酶体抑制剂联合使用时，细胞死亡明显增加。这些研究表明，促进受损蛋白形成的条件与蛋白酶体功能受损的条件之间存在协同效应，并进一步支持PD患者的细胞损失可能与蛋白质处理缺陷有关的观点。
Impairment in the capacity of the ubiquitin-proteasome pathway to clear unwanted proteins has been implicated in the cell death that occurs in Parkinson’s disease (PD). In support of this concept, defects in proteasomal structure and function, as well as protein aggregates and increased levels of oxidized proteins are found in the substantia nigra of PD patients. We have previously demonstrated that inhibition of proteasome activity in mesencephalic cultures induces degeneration of dopaminergic neurons coupled with the formation of proteinaceous intracellular inclusions. In this study we examined the effect of proteasome inhibition on cultured dopamine neurons when combined with oxidative stress and protein misfolding, in order to better simulate the condition in PD. We demonstrate that two structurally unrelated inhibitors of proteasome activity, lactacystin and carbobenzoxy-L-leucul-L-leucyl-L-leucinal (MG132), cause dose-dependent cell loss that preferentially affects dopaminergic neurons. Conditions that promote protein damage and misfolding such as oxidative stress, heat shock, and canavanine also induce neuronal degeneration with preferential loss of dopamine neurons and cell death is markedly increased when any of these is combined with a proteasome inhibitor. These studies demonstrate a synergistic effect between conditions that promote the formation of damaged proteins and those in which proteasomal function is impaired, and provide further support for the notion that cell loss in PD could be related to a defect in protein handling.