School of Health and Biomedical Sciences, King's College, London, UK.
Brain Res. 2010 Apr 22;1326:174-83. doi: 10.1016/j.brainres.2010.02.045. Epub 2010 Feb 20.
Dysfunction of the ubiquitin-proteasome system (UPS) occurs in dopaminergic neurones in the SN in PD and it is associated with Lewy body formation. However, it remains unknown whether this is specific to PD or whether it also occurs in multiple system atrophy (MSA) and progressive supranuclear palsy (PSP) where nigral dopaminergic neurones also degenerate. In the present study, we investigated changes in the expression of proteasomal subunits in the SN in PD, MSA and PSP. Immunohistochemistry double staining showed that proteasome 20S-alpha4 and -alpha6, and 20S-beta3 and -beta5i subunits are colocalized with tyrosine hydroxylase (TH)-positive cells in the SN of control, PD, MSA and PSP brain. Semi-quantitative analysis showed a significant loss of 20S-alpha4 and -alpha6 subunits TH-positive cells in PD, MSA and PSP compared to control tissue. There was no change in the expression of 20S-beta3 and -beta5i subunits in any of the disease states. The expression of PA700-Rpt5 subunits was not changed in PSP or PD but was significantly increased in MSA compared to control SN. PA700-Rpn10 subunit was not colocalized with TH within dopamine cells but was co-expressed with glial fibrillary acid protein (GFAP) positive astrocytes in the SN of all groups. PA28-alpha immunoreactivity was low in TH positive neurones in control tissue and quantification was not possible. Qualitative analysis suggested a decrease in PD and no immunoreactivity was detected in MSA or PSP. The results show that changes in proteasomal structure occur in the SN in PD, MSA and PSP and that these are similar in nature suggesting that dysfunction of UPS is not specific to PD or to Lewy body formation.
泛素-蛋白酶体系统（UPS）的功能障碍发生在 PD 患者的 SN 中的多巴胺能神经元中，并且与路易体形成有关。然而，目前尚不清楚这种情况是否是 PD 所特有的，还是也发生在多系统萎缩（MSA）和进行性核上性麻痹（PSP）中，其中黑质多巴胺能神经元也会退化。在本研究中，我们研究了 PD、MSA 和 PSP 中 SN 中蛋白酶体亚基表达的变化。免疫组织化学双重染色显示，蛋白酶体 20S-α4 和-α6 以及 20S-β3 和-β5i 亚基与 SN 中的酪氨酸羟化酶（TH）阳性细胞共定位。半定量分析显示，与对照组相比，PD、MSA 和 PSP 中的 20S-α4 和-α6 亚基 TH 阳性细胞明显减少。在任何疾病状态下，20S-β3 和-β5i 亚基的表达都没有变化。PA700-Rpt5 亚基在 PSP 或 PD 中没有变化，但在 MSA 中与对照组相比显著增加。PA700-Rpn10 亚基与多巴胺细胞内的 TH 没有共定位，但在所有组的 SN 中与胶质纤维酸性蛋白（GFAP）阳性星形胶质细胞共表达。PA28-α 在对照组组织中 TH 阳性神经元中的免疫反应性较低，无法进行定量分析。定性分析表明 PD 减少，而 MSA 或 PSP 中则没有免疫反应性。结果表明，在 PD、MSA 和 PSP 中 SN 中的蛋白酶体结构发生变化，其性质相似，表明 UPS 功能障碍不仅是 PD 所特有的，也不仅与路易体形成有关。
