Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia.
Elevated tauopathy and alpha-synuclein pathology in postmortem Parkinson's disease brains with and without dementia.
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DOI：
10.1016/j.expneurol.2010.06.017
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发表时间：
2010-09
影响因子：
5.3
通讯作者：
Sidhu, Anita
中科院分区：
文献类型：
--
作者：
Wills, Jonathan;Jones, Jessica;Haggerty, Thomas;Duka, Valeriy;Joyce, Jeffrey N.;Sidhu, Anita
关键词：
帕金森病（PD）是一种进行性神经退行性疾病，导致多巴胺能神经元中不溶性α-突触核蛋白[α-Syn]的异常积累。在这里，我们检测了PD和PD合并痴呆患者死后纹状体和额下回（IFG）的病变变化和α-Syn/p-GSK-3β/蛋白酶体通路。在PD和PDD中，α-Syn水平均较高，尤其是该蛋白的不溶性形式；在PDD中，两脑区的不溶性α-Syn水平持续高于PD。在Tyr 216位点磷酸化的p-GSK-3β水平，与对照组相比，PD和PDD的纹状体中p-GSK-3β水平更高，而在IFG中则没有变化。虽然PD和PDD的纹状体中蛋白酶体活性不变，但PD和PDD的IFG中蛋白酶体活性均降低。PDD患者IFG中蛋白酶体19S亚基降低，而PD和PDD患者纹状体和IFG中20S亚基水平均降低。帕金蛋白水平在PD和PDD中相似，提示缺乏这种蛋白的参与。最有趣的是，仅在PD和PDD的纹状体中发现了头部病变，Ser262和Ser396/404位点的过度磷酸化增加；Ser202水平仅在PD中升高，而在PDD纹状体中未见升高。尽管α-Syn水平升高，蛋白酶体活性降低，但PD或PDD患者的IFG中均未检测到任何tau病变，这可能是由于IFG中p-GSK-3β缺乏增加。与阿尔茨海默病不同的是，在不同的大脑区域更广泛地观察到脑损伤，我们的数据表明PD和PDD大脑中脑损伤的表达有限，可能仅限于黑质纹状体区域的多巴胺能神经元。
Parkinson’s disease [PD], a progressive neurodegenerative disease, results in abnormal accumulation of insoluble alpha-synuclein [α-Syn] in dopaminergic neurons. Here we examined tauopathic changes and the α-Syn/p-GSK-3β/proteasome pathway in postmortem striata and inferior frontal gyri [IFG] from patients with PD and PD with dementia [PDD]. In both PD and PDD, α-Syn levels were high, especially the insoluble form of this protein; in PDD, insoluble α-Syn levels were persistently higher than PD across both brain regions. Levels of p-GSK-3β phosphorylated at Tyr 216, which hyperphosphorylates Tau to produce toxic pathological forms of p-Tau, were higher in striata of both PD and PDD compared to controls, but were unaltered in IFG. While proteasomal activity was unchanged in striatum of PD and PDD, such activity was diminished in the IFG of both PD and PDD. A decrease in 19S subunit of the proteasomes was seen in IFG of PDD, while lower levels of 20S subunits were seen in striatum and IFG of both PD and PDD patients. Parkin levels were similar in PD and PDD, suggesting lack of involvement of this protein. Most interestingly, tauopathic changes were noted only in striatum of PD and PDD, with increased hyperphosphorylation seen at Ser262 and Ser396/404; increases in Ser202 levels were seen only in PD but not in PDD striatum. We were unable to detect any tauopathy in IFG in either PD or PDD despite increased levels of α-Syn, and decreased proteasomal activity, and is probably due to lack of increase in p-GSK-3β in IFG. Unlike Alzheimer’s disease where tauopathy is more globally observed in diverse brain regions, our data demonstrates restricted expression of tauopathy in brains of PD and PDD, probably limited to dopaminergic neurons of the nigrostriatal region.
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影响因子：
9.3
作者：
Griffin, W. Sue T.;Liu, Ling;Barger, Steven W.
通讯作者：
Barger, Steven W.
影响因子：
2.9
作者：
Joyce, JN;Ryoo, HL;Adler, CH
通讯作者：
Adler, CH
影响因子：
3.3
作者：
Muntane, G.;Dalfo, E.;Ferrer, I.
通讯作者：
Ferrer, I.
DOI：
10.1016/0169-328x(95)00111-5
发表时间：
1995-12-01
期刊：
MOLECULAR BRAIN RESEARCH
影响因子：
--
作者：
BAUM, L;SEGER, R;SAITOH, T
通讯作者：
SAITOH, T
影响因子：
5
作者：
Hishikawa, N;Hashizume, Y;Sobue, G
通讯作者：
Sobue, G