Usp14 deficiency increases tau phosphorylation without altering tau degradation or causing tau-dependent deficits.
Usp14 deficiency increases tau phosphorylation without altering tau degradation or causing tau-dependent deficits.
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DOI：
10.1371/journal.pone.0047884
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Wilson SM
中科院分区：
文献类型：
--
作者：
Jin YN;Chen PC;Watson JA;Walters BJ;Phillips SE;Green K;Schmidt R;Wilson JA;Johnson GV;Roberson ED;Dobrunz LE;Wilson SM
由蛋白酶体调节的蛋白质降解在神经系统中信号通路的增强和抑制中起着重要作用。蛋白酶体相关因子在确保适当的蛋白质降解中是关键的，我们以前已经证明，这些因子之一，蛋白酶体去泛素化酶泛素特异性蛋白酶14（Usp 14）的改变，可导致蛋白酶体功能障碍和神经系统疾病。最近在细胞培养中的研究表明，Usp 14还可以稳定过度表达的疾病相关蛋白质如tau和共济失调蛋白-3的表达。使用Usp 14缺陷型axJ小鼠，我们研究了Usp 14的缺失是否会导致小鼠神经系统中内源性tau和共济失调蛋白-3水平的降低。尽管Usp 14的缺失并没有改变tau蛋白和共济失调蛋白-3的整体神经元水平，但我们发现磷酸化tau蛋白水平的增加与Usp 14缺陷小鼠轴突静脉曲张的发生相关。tau蛋白磷酸化的这些变化伴随着激活的磷酸化Akt、磷酸化MAPK和失活的磷酸化GSK 3 β水平的增加。然而，tau的基因消融并没有改变Usp 14缺陷小鼠的任何神经缺陷，这表明磷酸化tau水平的增加并不一定会导致神经系统疾病。由于Usp 14的缺失引起的细胞内信号通路的广泛激活，在有效的基于蛋白酶体的疗法可用于治疗慢性神经系统疾病之前，需要更好地理解由蛋白酶体调节的细胞通路。
Regulated protein degradation by the proteasome plays an essential role in the enhancement and suppression of signaling pathways in the nervous system. Proteasome-associated factors are pivotal in ensuring appropriate protein degradation, and we have previously demonstrated that alterations in one of these factors, the proteasomal deubiquitinating enzyme ubiquitin-specific protease 14 (Usp14), can lead to proteasome dysfunction and neurological disease. Recent studies in cell culture have shown that Usp14 can also stabilize the expression of over-expressed, disease-associated proteins such as tau and ataxin-3. Using Usp14-deficient axJ mice, we investigated if loss of Usp14 results in decreased levels of endogenous tau and ataxin-3 in the nervous system of mice. Although loss of Usp14 did not alter the overall neuronal levels of tau and ataxin-3, we found increased levels of phosphorylated tau that correlated with the onset of axonal varicosities in the Usp14-deficient mice. These changes in tau phosphorylation were accompanied by increased levels of activated phospho-Akt, phosphorylated MAPKs, and inactivated phospho-GSK3β. However, genetic ablation of tau did not alter any of the neurological deficits in the Usp14-deficient mice, demonstrating that increased levels of phosphorylated tau do not necessarily lead to neurological disease. Due to the widespread activation of intracellular signaling pathways induced by the loss of Usp14, a better understanding of the cellular pathways regulated by the proteasome is required before effective proteasomal-based therapies can be used to treat chronic neurological diseases.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
5.3
作者：
Crimmins, Stephen;Jin, Youngam;Wilson, Scott M.
通讯作者：
Wilson, Scott M.
DOI：
10.1074/mcp.r110.003871
发表时间：
2011-05-01
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Lee, Min Jae;Lee, Byung-Hoon;Finley, Daniel
通讯作者：
Finley, Daniel
影响因子：
16.6
作者：
Finley D
通讯作者：
Finley D
影响因子：
11.4
作者：
BIERNAT, J;MANDELKOW, EM;MANDELKOW, E
通讯作者：
MANDELKOW, E