Genetic background alters the severity and onset of neuromuscular disease caused by the loss of ubiquitin-specific protease 14 (usp14).
Genetic background alters the severity and onset of neuromuscular disease caused by the loss of ubiquitin-specific protease 14 (usp14).
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DOI：
10.1371/journal.pone.0084042
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发表时间：
2013
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：
Marshall AG;Watson JA;Hallengren JJ;Walters BJ;Dobrunz LE;Francillon L;Wilson JA;Phillips SE;Wilson SM
在这项研究中，我们确定并表征了N-乙基-N-亚硝基脲（ENU）诱导的Usp 14（nmf 375）突变，该突变导致成人发病的神经系统疾病。nmf 375突变导致Usp 14 mRNA的异常剪接，导致USP 14减少95%。我们先前表明，在共济失调（ax J）小鼠中USP 14的缺失导致在生命的前4-6周内泛素水平降低、运动终板疾病、浦肯野细胞轴突营养不良和海马成对脉冲易化（PPF）降低，以及出生后两个月龄的早期致死。尽管nmf 375和ax J小鼠之间的USP 14丢失相当，但nmf 375小鼠未表现出这些ax J发育异常。然而，到12周龄时，nmf 375突变体出现泛素耗竭和运动终板疾病，表明USP 14介导的成年小鼠泛素库和神经肌肉接头（NMJ）结构调节的持续作用。运动终板疾病仅见于泛素耗竭后的观察结果表明，NMJ结构的保存需要突触泛素池的稳定维持。遗传背景的差异被证明会影响泛素的表达，并显着改变由USP 14缺陷引起的表型。
In this study, we identified and characterized an N-ethyl-N-nitrosourea (ENU) induced mutation in Usp14 (nmf375) that leads to adult-onset neurological disease. The nmf375 mutation causes aberrant splicing of Usp14 mRNA, resulting in a 95% reduction in USP14. We previously showed that loss of USP14 in ataxia (ax J) mice results in reduced ubiquitin levels, motor endplate disease, Purkinje cell axonal dystrophy and decreased hippocampal paired pulse facilitation (PPF) during the first 4-6 weeks of life, and early postnatal lethality by two months of age. Although the loss of USP14 is comparable between the nmf375 and ax J mice, the nmf375 mice did not exhibit these ax J developmental abnormalities. However, by 12 weeks of age the nmf375 mutants present with ubiquitin depletion and motor endplate disease, indicating a continual role for USP14-mediated regulation of ubiquitin pools and neuromuscular junction (NMJ) structure in adult mice. The observation that motor endplate disease was only seen after ubiquitin depletion suggests that the preservation of NMJ structure requires the stable maintenance of synaptic ubiquitin pools. Differences in genetic background were shown to affect ubiquitin expression and dramatically alter the phenotypes caused by USP14 deficiency.
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DOI：
10.1523/jneurosci.2635-09.2009
发表时间：
2009-09-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen PC;Qin LN;Li XM;Walters BJ;Wilson JA;Mei L;Wilson SM
通讯作者：
Wilson SM
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.
影响因子：
5.5
作者：
Bhattacharyya, Bula J.;Wilson, Scott M.;Miller, Richard J.
通讯作者：
Miller, Richard J.
影响因子：
16
作者：
Leggett, DS;Hanna, J;Finley, D
通讯作者：
Finley, D