Protective role of heat shock and heat shock protein 70 in lactacystin-induced cell death both in the rat substantia nigra and PC12 cells
Protective role of heat shock and heat shock protein 70 in lactacystin-induced cell death both in the rat substantia nigra and PC12 cells
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DOI：
10.1016/j.brainres.2006.02.097
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发表时间：
2006-05-04
期刊：
影响因子：
2.9
通讯作者：
Jeon, Beom S.
中科院分区：
文献类型：
--
作者：
Ahn, Tae-Beom;Jeon, Beom S.
蛋白酶体功能障碍在帕金森病(PD)的发病机制中起重要作用。尽管越来越多的临床和实验证据表明热休克蛋白70(HSP70)在帕金森病的发病机制中起重要作用，但很少有人研究HSP70在蛋白酶体功能障碍中的作用。在体内研究中，我们向有或没有全身热疗(WBH)的SD大鼠的单侧黑质(SN)内注入lactacystin。免疫组织化学研究显示黑质内多巴胺能神经元死亡，小胶质细胞激活。Lactacystin与WBH联合应用较单独应用Lactacystin更能增加黑质HSP70的表达，并减少Lactacystin诱导的黑质多巴胺能神经元死亡。在PC12细胞中，热休克预处理可减少lactacystin诱导的细胞死亡。虽然诺康唑、氯化铵和3-甲基腺嘌呤的额外处理增加了lactacystin对细胞的死亡，但热休克预处理。来抵消这些药物的额外毒性。这些结果表明，热休克蛋白，尤其是HSP70，可能通过促进侵袭体的形成和溶酶体介导的自噬而在蛋白酶体功能障碍的条件下发挥重要作用。(C)2006爱思唯尔B.V.保留所有权利。
Proteasomal dysfunction plays an important role in the pathogenesis of Parkinson disease (PD). Although clinical and experimental evidence continues to accumulate indicating heat shock protein 70 (HSP70) is significant in the pathogenesis of PD, few studies have been made to investigate the role of HSP70 under the condition of proteasome dysfunction. In in vivo study, we infused lactacystin into the unilateral substantia nigra (SN) of Sprague-Dawley rats with or without preceding whole body hyperthermia (WBH). Immunohistochemical studies showed the death of dopaminergic neurons and activated microglia in the SN. Lactacystin with prior WBH increased the expression of HSP70 more than did lactacystin alone and decreased lactacystin-induced dopaminergic neuronal death in the SN. In PC12 cells, heat shock pretreatment decreased lactacystin-induced cell death. Although additional treatment of nocodazole, ammonium chloride, and 3-methyladenine augmented cell death by lactacystin, heat shock pretreated. to these drugs offsets their additional toxicity. These results indicate that heat shock proteins, especially HSP70, could play an important role under the condition of proteasome dysfunction in part by fostering aggresome formation and lysosome-mediated autophagy. (c) 2006 Elsevier B.V. All rights reserved.