Ahn Tae-Beom, Jeon Beom S
Department of Neurology, Kyung Hee University College of Medicine, South Korea.
Brain Res. 2006 May 4;1087(1):159-67. doi: 10.1016/j.brainres.2006.02.097. Epub 2006 Apr 13.
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.
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。尽管临床和实验证据不断积累，表明热休克蛋白70（HSP70）在PD发病机制中具有重要意义，但很少有研究探讨蛋白酶体功能障碍条件下HSP70的作用。在体内研究中，我们将乳胞素注入有或无前全身热疗（WBH）的Sprague-Dawley大鼠单侧黑质（SN）。免疫组织化学研究显示SN中多巴胺能神经元死亡和小胶质细胞活化。与单独使用乳胞素相比，预先进行WBH的乳胞素增加了HSP70的表达，并减少了乳胞素诱导的SN中多巴胺能神经元死亡。在PC12细胞中，热休克预处理减少了乳胞素诱导的细胞死亡。尽管用诺考达唑、氯化铵和3-甲基腺嘌呤进行额外处理会增加乳胞素诱导的细胞死亡，但对这些药物进行热休克预处理可抵消其额外毒性。这些结果表明，热休克蛋白，尤其是HSP70，在蛋白酶体功能障碍条件下可能通过促进聚集体形成和溶酶体介导的自噬发挥重要作用。
