论文摘要
目的:研究自噬/溶酶体途径在6-羟基多巴胺（6-OHDA）致多巴胺能神经细胞死亡中的作用,探讨自噬在帕金森病发病中的机制。方法:采用脑立体定位黑质致密部给药法,建立6-OHDA介导的帕金森病大鼠模型;采用6-OHDA处理人神经母细胞瘤株SH-SY5Y细胞建立PD细胞模型。利用透射电镜和MDC染色法观察DA神经细胞中自噬和溶酶体的激活,免疫荧光法和Western Blot法检测6-OHDA对DA神经细胞中自噬、溶酶体和凋亡相关蛋白表达的影响,以及抑制自噬和溶酶体对这些蛋白表达的影响。结果:透射电镜显示,6-OHDA给药后1.5h至24h可见大鼠黑质致密部神经元内溶酶体被激活,自噬小体形成,24h自噬和凋亡同时存在。MDC染色发现6-OHDA能诱导SH-SY5Y细胞产生自噬小泡。免疫荧光法显示模型大鼠与对照组相比,cathepsin L、cathepsin B、Lamp1阳性细胞增多,cathepsin L出现核异位表达。3-MA能增加TH阳性细胞数量,显著降低cathepsin L的表达,明显减少NF-κB p65核转位和TUNEL阳性细胞数。在PD细胞模型中,LC3表达量增加,Cathepsin L被激活,在细胞核内大量表达,几乎同一时程,NF-κB p65也大量核转位;自噬抑制剂3-MA、溶酶体碱化试剂NH4Cl能增加6-OHDA早期的细胞毒性,减轻晚期的细胞毒性。3-MA、NH4Cl和组织蛋白酶抑制剂Leupeptin能减少LC3表达量,Leupeptin能下调cathepsin L的表达。结论: 6-OHDA介导的多巴胺能神经细胞死亡与溶酶体的激活及自噬的发生有关。在损伤发生早期,自噬可作为一种保护机制抵御氧化应激对神经细胞造成的损伤,在后期自噬通过激活溶酶体,与NF-κB介导的神经元凋亡通路相关联,共同调控神经细胞死亡。
论文目录
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标签：自噬论文; 溶酶体论文; 帕金森病论文; 多巴胺能神经细胞论文; 羟基多巴胺论文;