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α-突触核蛋白(α-synuclein,α-SN)和泛素-蛋白酶体系统(ubiquitin-proteasome system,UPS)在帕金森病发病过程中都起着重要作用,探讨两者在多巴胺能神经细胞死亡过程中的相互关系有重要意义。本文分别采用不同浓度的重组人α-SN、蛋白酶体活性抑制剂lactacystin单独处理,或与多巴胺能神经细胞特异毒素6-羟基多巴胺(6-OHDA)联合处理多巴胺能神经细胞系SH-SY5Y细胞,然后检测细胞活性和蛋白酶体活性。结果显示,α-SN依据浓度的不同而具有神经保护或神经毒性的双重作用。5μmol/L以下浓度的α-SN可对抗6-OHDA对SH-SY5Y细胞的毒性,并有一定促增殖作用;10μmol/L以上浓度的α-SN对细胞有毒性作用,并加重了6-OHDA的细胞毒性。采用相应浓度的lactacystin处理,获得与α-SN处理相似的结果,而MEK1/2特异抑制剂PD98059干预则可完全阻断低浓度α-SN和lactacystin的神经保护作用。以上结果提示,不同浓度α-SN对SH-SY5Y细胞的6-OHDA神经毒性的双重作用是通过抑制蛋白酶体活性实现的,而其对神经细胞的保护作用和MAPK途径相关。
α-synuclein (α-SN) and ubiquitin-proteasome system (UPS) play an important role in the pathogenesis of Parkinson’s disease, and their roles in dopaminergic neuropathy The relationship between cell death process is of great significance. In this study, SH-SY5Y cells were treated with different concentrations of recombinant human α-SN and proteasome inhibitor lactacystin alone or in combination with dopaminergic neurotoxin-6-hydroxydopamine (6-OHDA) Then cell activity and proteasome activity were examined. The results showed that α-SN has the dual role of neuroprotection or neurotoxicity depending on the concentration. The concentration of α-SN of 5μmol / L could antagonize the toxicity of 6-OHDA to SH-SY5Y cells and promote the proliferation of the cells. Α-SN of more than 10μmol / L could increase the toxicity of 6-OHDA Cytotoxicity. The same concentration of lactacystin treatment, and α-SN treatment similar results, while the MEK1 / 2 inhibitor PD98059 intervention can completely block the low concentration of α-SN and lactacystin neuroprotection. The above results suggest that the dual effect of different concentrations of α-SN on 6-OHDA neurotoxicity in SH-SY5Y cells is through inhibition of proteasome activity, and its protective effect on nerve cells is related to MAPK pathway.