Ataxin-3 and its e3 partners: implications for machado-joseph disease.
Ataxin-3 and its e3 partners: implications for machado-joseph disease.
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DOI：
10.3389/fneur.2013.00046
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发表时间：
2013
影响因子：
3.4
通讯作者：
Fon EA
中科院分区：
文献类型：
--
作者：
Durcan TM;Fon EA
Machado-Joseph病（MJD）是世界范围内最常见的显性遗传性共济失调，由SCA 3基因内不稳定的CAG三核苷酸扩增突变引起，导致共济失调蛋白-3蛋白内多聚谷氨酰胺束扩增。共济失调蛋白-3在Ub系统中作为去泛素化酶（DUB）发挥作用，尽管已知许多DUB与特异性E3-Ub连接酶配对并使其去泛素化，但共济失调蛋白-3直到最近的研究涉及两种神经保护性E3连接酶parkin和CHIP才确定E3配对物。MJD通常表现为帕金森病（PD）的症状，这导致将parkin鉴定为一种新的E3-Ub连接酶，其活性受ataxin-3介导的去泛素化调节。这些研究的结果还揭示了E2-Ub结合酶在E3/DUB酶对调节中的意想不到的收敛。此外，突变型而非野生型共济失调蛋白-3通过自噬途径促进parkin的清除，提出了一种有趣的可能性，即parkin的周转增加可能有助于MJD的发病机制，并有助于解释MJD中的一些帕金森病特征。除了parkin，U-box E3连接酶CHIP，一种涉及蛋白质质量控制的神经保护性E3，被鉴定为共济失调蛋白-3的第二个E3伴侣，共济失调蛋白-3调节CHIP自身泛素化的能力。事实上，共济失调蛋白-3不仅去泛素化CHIP，而且还修剪CHIP底物上的Ub缀合物，从而调节Ub链的长度。有趣的是，当存在扩展的共济失调蛋白-3时，MJD转基因小鼠脑中的CHIP水平也降低，这增加了一个或两个E3伴侣的丢失可能是SCA 3发病机制中的一个促成因素的可能性。在这篇综述中，我们讨论了这些研究的意义，并描述了这些发现的重要性，帮助我们了解SCA 3和其他神经退行性疾病的分子过程。
Machado–Joseph disease (MJD) is the most common dominant inherited ataxia worldwide, caused by an unstable CAG trinucleotide expansion mutation within the SCA3 gene resulting in an expanded polyglutamine tract within the ataxin-3 protein. Ataxin-3 functions as a deubiquitinating enzyme (DUB), within the Ub system and whilst many DUBs are known to partner with and deubiquitinate specific E3-Ub ligases, ataxin-3 had no identified E3 partner until recent studies implicated parkin and CHIP, two neuroprotective E3 ligases. MJD often presents with symptoms of Parkinson disease (PD), which led to identification of parkin as a novel E3-Ub ligase whose activity was regulated by ataxin-3-mediated deubiquitination. Findings from these studies also revealed an unexpected convergence upon the E2-Ub-conjugating enzyme in the regulation of an E3/DUBenzyme pair. Moreover, mutant but not wild-type ataxin-3 promotes the clearance of parkin via the autophagy pathway, raising the intriguing possibility that increased turnover of parkin may contribute to the pathogenesis of MJD and help explain some of the Parkinsonian features in MJD. In addition to parkin, the U-box E3 ligase CHIP, a neuroprotective E3 implicated in protein quality control, was identified as a second E3 partner of ataxin-3, with ataxin-3 regulating the ability of CHIP to ubiquitinate itself. Indeed, ataxin-3 not only deubiquitinated CHIP, but also trimmed Ub conjugates on CHIP substrates, thereby regulating the length of Ub chains. Interestingly, when expanded ataxin-3 was present, CHIP levels were also reduced in the brains of MJD transgenic mice, raising the possibility that loss of one or both E3 partners may be a contributing factor in the pathogenesis of SCA3. In this review we discuss the implications from these studies and describe the importance of these findings in helping us understand the molecular processes involved in SCA3 and other neurodegenerative disorders.
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发表时间：
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影响因子：
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