In AbetaPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis.
In AbetaPP-overexpressing cultured human muscle fibers proteasome inhibition enhances phosphorylation of AbetaPP751 and GSK3beta activation: effects mitigated by lithium and apparently relevant to sporadic inclusion-body myositis.
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DOI：
10.1111/j.1471-4159.2009.06461.x
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发表时间：
2010-01
影响因子：
4.7
通讯作者：
Askanas V
中科院分区：
文献类型：
--
作者：
Terracciano C;Nogalska A;Engel WK;Askanas V
散发性包涵体肌炎（s-IBM）中的肌纤维变性的特征在于多蛋白聚集体的积累，包括聚集的淀粉样蛋白-β-前体蛋白751（Aβ PP 751）、淀粉样蛋白-β（Aβ）、磷酸化tau（p-tau）和其他“阿尔茨海默特征性”蛋白。蛋白酶体抑制是s-IBM发病机制的重要组成部分。在阿尔茨海默病（AD）患者和AD转基因小鼠模型的脑中，苏氨酸668（T668）（相当于Aβ PP 751的T724）上神经元Aβ PP 695（p-AβPP）的磷酸化被认为是有害的，因为它会增加细胞毒性Aβ的生成并诱导tau磷酸化。活化的糖原合成酶激酶3 β（GSK 3 β）参与AβPP和tau蛋白的磷酸化。据报道，锂（一种GSK 3 β抑制剂）可降低AD动物模型中总AβPP和p-AβPP的水平。关于s-IBM，我们现在第一次证明：1。在Aβ PP过表达培养的人肌纤维（人肌肉培养物IBM模型）中：a）蛋白酶体抑制显著增加GSK 3 β活性和AβPP磷酸化; B）锂处理降低i）磷酸化-A βPP; ii）AβPP总量，iii）Aβ寡聚体和iv）GSK 3 β活性; c）锂改善蛋白酶体功能。2.在活检的s-IBM肌纤维中，GSK 3 β显著活化，AβPP在Thr 724上磷酸化。因此，锂或其他GSK 3 β抑制剂治疗可能使s-IBM患者受益。
Muscle fiber degeneration in sporadic inclusion-body myositis (s-IBM) is characterized by accumulation of multiprotein aggregates, including aggregated amyloid-β-precursor protein 751 (AβPP751), amyloid-β (Aβ), phosphorylated tau (p-tau), and other “Alzheimer-characteristic” proteins. Proteasome inhibition is an important component of the s-IBM pathogenesis. In brains of Alzheimer disease (AD) patients and AD transgenic mouse models, phosphorylation of neuronal AβPP695 (p-AβPP) on Threonine668 (T668) (equivalent to T724 of AβPP751) is considered detrimental because it increases generation of cytotoxic Aβ and induces tau phosphorylation. Activated glycogen synthase kinase3β (GSK3β) is involved in phosphorylation of both AβPP and tau. Lithium, an inhibitor of GSK3β, was reported to reduce levels of both the total AβPP and p-AβPP in AD animal models. In relation to s-IBM, we now show for the first time that: 1. In AβPP-overexpressing cultured human muscle fibers (human muscle culture IBM model: a) proteasome inhibition significantly increases GSK3β activity and AβPP phosphorylation; b) treatment with lithium decreases i) phosphorylated-AβPP; ii) total amount of AβPP, iii) Aβ oligomers, and iv) GSK3β activity; and c) lithium improves proteasome function. 2. In biopsied s-IBM muscle fibers, GSK3β is significantly activated and AβPP is phosphorylated on Thr724. Accordingly, treatment with lithium, or other GSK3β inhibitors, might benefit s-IBM patients.
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DOI：
10.1083/jcb.200301115
发表时间：
2003-10-13
期刊：
The Journal of cell biology
影响因子：
--
作者：
Lee MS;Kao SC;Lemere CA;Xia W;Tseng HC;Zhou Y;Neve R;Ahlijanian MK;Tsai LH
通讯作者：
Tsai LH
影响因子：
6
作者：
Fratta, P;Engel, WK;Askanas, V
通讯作者：
Askanas, V
影响因子：
16
作者：
Lochhead, Pamela A.;Kinstrie, Ross;Cleghon, Vaughn
通讯作者：
Cleghon, Vaughn
DOI：
10.1523/jneurosci.1150-09.2009
发表时间：
2009-05-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Kitazawa M;Vasilevko V;Cribbs DH;LaFerla FM
通讯作者：
LaFerla FM
影响因子：
6
作者：
Jin, LW;Hearn, MG;Martin, GM
通讯作者：
Martin, GM