Toward understanding Machado-Joseph disease.
Toward understanding Machado-Joseph disease.
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DOI：
10.1016/j.pneurobio.2011.11.006
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发表时间：
2012-05
影响因子：
6.7
通讯作者：
Paulson, Henry L.
中科院分区：
文献类型：
--
作者：
Costa, Maria do Carmo;Paulson, Henry L.
关键词：
马查多-约瑟夫病（MJD），也称为脊髓小脑共济失调3型（SCA 3），是最常见的遗传性脊髓小脑共济失调，也是许多多聚谷氨酰胺神经退行性疾病之一。在MJD中，CAG重复扩增编码疾病蛋白ATXN 3中异常长的多聚谷氨酰胺（polyQ）道。在这里，我们回顾MJD，主要集中在ATXN 3的功能和功能障碍，并对潜在的治疗进展。ATXN 3是一种去泛素化酶（DUB），其高度特化的特性表明它参与了泛素依赖的蛋白质稳态。凭借其与VCP，各种泛素连接酶和其他泛素连接蛋白的相互作用，ATXN 3可能有助于调节蛋白毒性应激反应，衰老和细胞分化中涉及的多种细胞途径中许多蛋白质的稳定性或活性。ATXN 3中polyQ区的扩展被认为促进蛋白质中构象的改变，导致与天然伴侣的相互作用的变化以及不溶性聚集体的形成。广泛的MJD细胞和动物模型的开发对于polyQ扩增后ATXN 3功能障碍的新兴理解至关重要。然而，尽管取得了许多进展，突变体ATXN 3引起神经毒性的主要分子机制仍然难以捉摸。在像MJD这样的慢性退行性疾病中，可以想象突变体ATXN 3触发多个相互关联的致病级联反应，从而导致细胞功能障碍和最终的细胞死亡。更好地了解这些复杂的分子机制将是重要的，因为科学家和临床医生开始专注于开发这种无法治愈的致命疾病的有效疗法。
Machado-Joseph disease (MJD), also known as Spinocerebellar ataxia type 3 (SCA3), is the most common inherited spinocerebellar ataxia and one of many polyglutamine neurodegenerative diseases. In MJD, a CAG repeat expansion encodes an abnormally long polyglutamine (polyQ) tract in the disease protein, ATXN3. Here we review MJD, focusing primarily on the function and dysfunction of ATXN3 and on advances toward potential therapies. ATXN3 is a deubiquitinating enzyme (DUB) whose highly specialized properties suggest that it participates in ubiquitin-dependent proteostasis. By virtue of its interactions with VCP, various ubiquitin ligases and other ubiquitin-linked proteins, ATXN3 may help regulate the stability or activity of many proteins in diverse cellular pathways implicated in proteotoxic stress response, aging, and cell differentiation. Expansion of the polyQ tract in ATXN3 is thought to promote an altered conformation in the protein, leading to changes in interactions with native partners and to the formation of insoluble aggregates. The development of a wide range of cellular and animal models of MJD has been crucial to the emerging understanding of ATXN3 dysfunction upon polyQ expansion. Despite many advances, however, the principal molecular mechanisms by which mutant ATXN3 elicits neurotoxicity remain elusive. In a chronic degenerative disease like MJD, it is conceivable that mutant ATXN3 triggers multiple, interconnected pathogenic cascades that precipitate cellular dysfunction and eventual cell death. A better understanding of these complex molecular mechanisms will be important as scientists and clinicians begin to focus on developing effective therapies for this incurable, fatal disorder.
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影响因子：
3.5
作者：
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通讯作者：
de Almeida, Luis Pereira
影响因子：
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Berke, SJS;Schmied, FAF;Paulson, HL
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Paulson, HL
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Riess, Olaf
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通讯作者：
Pittman, RN
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通讯作者：
Riess, Olaf