An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis.
An emerging role for misfolded wild-type SOD1 in sporadic ALS pathogenesis.
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DOI：
10.3389/fncel.2013.00253
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发表时间：
2013-12-16
影响因子：
5.3
通讯作者：
Bosco DA
中科院分区：
文献类型：
--
作者：
Rotunno MS;Bosco DA
肌萎缩性侧索硬化症（ALS）是一种致命的神经退行性疾病，以运动神经元为目标，在发病几年内导致瘫痪和死亡。虽然有几个基因与遗传性或家族性ALS有关，但对散发性ALS的病因知之甚少，散发性ALS约占ALS病例的90%。由于家族性和散发性肌萎缩侧索硬化症的临床相似之处，这两种形式的疾病似乎汇聚在一个共同的途径上，因此涉及共同的因素。最近的证据表明，Cu， zn -超氧化物歧化酶（SOD1）蛋白是散发性和家族性ALS中常见的一个因素。1993年，SOD1突变被发现，这是家族性ALS的第一个已知遗传原因。虽然突变sod1毒性的确切机制至今仍不为人所知，但大多数证据表明，至少在一定程度上，这种蛋白质的错误折叠倾向导致了毒性功能的增加。在野生型SOD1蛋白中，非遗传扰动（如金属缺失、四级结构破坏和氧化）也可诱导SOD1错误折叠。事实上，上述这些翻译后修饰导致野生型SOD1采用类似于家族性als相关SOD1变体的“毒性构象”。这些观察结果，再加上在人类死后散发性ALS样本中检测到错误折叠的野生型SOD1，已被用来支持有争议的假设，即错误折叠的野生型SOD1有助于散发性ALS的发病机制。在这篇综述中，我们提出了支持和反驳这一假设的文献数据。我们还讨论了SOD1作为家族性和散发性ALS的潜在治疗靶点。
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that targets motor neurons, leading to paralysis and death within a few years of disease onset. While several genes have been linked to the inheritable, or familial, form of ALS, much less is known about the cause(s) of sporadic ALS, which accounts for ~90% of ALS cases. Due to the clinical similarities between familial and sporadic ALS, it is plausible that both forms of the disease converge on a common pathway and, therefore, involve common factors. Recent evidence suggests the Cu,Zn-superoxide dismutase (SOD1) protein to be one such factor that is common to both sporadic and familial ALS. In 1993, mutations were uncovered in SOD1 that represent the first known genetic cause of familial ALS. While the exact mechanism of mutant-SOD1 toxicity is still not known today, most evidence points to a gain of toxic function that stems, at least in part, from the propensity of this protein to misfold. In the wild-type SOD1 protein, non-genetic perturbations such as metal depletion, disruption of the quaternary structure, and oxidation, can also induce SOD1 to misfold. In fact, these aforementioned post-translational modifications cause wild-type SOD1 to adopt a “toxic conformation” that is similar to familial ALS-linked SOD1 variants. These observations, together with the detection of misfolded wild-type SOD1 within human post-mortem sporadic ALS samples, have been used to support the controversial hypothesis that misfolded forms of wild-type SOD1 contribute to sporadic ALS pathogenesis. In this review, we present data from the literature that both support and contradict this hypothesis. We also discuss SOD1 as a potential therapeutic target for both familial and sporadic ALS.
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