Mechanisms, models and biomarkers in amyotrophic lateral sclerosis.
Mechanisms, models and biomarkers in amyotrophic lateral sclerosis.
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DOI：
10.3109/21678421.2013.778554
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发表时间：
2013-05
影响因子：
2.8
通讯作者：
Fischbeck KH
中科院分区：
文献类型：
--
作者：
Turner MR;Bowser R;Bruijn L;Dupuis L;Ludolph A;McGrath M;Manfredi G;Maragakis N;Miller RG;Pullman SL;Rutkove SB;Shaw PJ;Shefner J;Fischbeck KH
在过去的30年里，人们对肌萎缩侧索硬化症（ALS）的临床和病理异质性及其与额颞叶痴呆的重叠的理解取得了重大进展。多个看似不同的生化途径汇聚在一个共同的临床综合征，其特征是上、下运动神经元的进行性丧失。ALS的致病主题包括兴奋性毒性、氧化应激、线粒体功能障碍、神经炎症、能量代谢改变以及最近的RNA错误加工。过表达突变型超氧化物歧化酶-1的转基因啮齿动物现在只是ALS发病机制的几种模型之一。线虫，果蝇和斑马鱼都提供了新的见解，诱导多能干细胞衍生的运动神经元的发展为候选疗法的筛选带来了希望。ALS中缺乏有用的生物标志物导致诊断延迟，并且无法通过预后对患者进行分层可能是治疗试验失败的重要因素。对疾病活动敏感的生物标志物可能会减少对临床指标和生存率作为试验终点的依赖，并缩短研究时间。脑脊液中神经元丢失和胶质细胞活性的新兴蛋白质组标记物，来自高级结构和功能MRI的皮质特征，以及更灵敏的下运动神经元生理学测量的发展正在引领生物标记物驱动的治疗发现的新阶段。
The last 30 years have seen a major advance in the understanding of the clinical and pathological heterogeneity of amyotrophic lateral sclerosis (ALS), and its overlap with frontotemporal dementia. Multiple, seemingly disparate biochemical pathways converge on a common clinical syndrome characterized by progressive loss of upper and lower motor neurons. Pathogenic themes in ALS include excitotoxicity, oxidative stress, mitochondrial dysfunction, neuroinflammation, altered energy metabolism, and most recently RNA mis-processing. The transgenic rodent, overexpressing mutant superoxide dismutase-1, is now only one of several models of ALS pathogenesis. The nematode, fruit fly and zebrafish all offer fresh insight, and the development of induced pluripotent stem cell-derived motor neurons holds promise for the screening of candidate therapeutics. The lack of useful biomarkers in ALS contributes to diagnostic delay, and the inability to stratify patients by prognosis may be an important factor in the failure of therapeutic trials. Biomarkers sensitive to disease activity might lessen reliance on clinical measures and survival as trial endpoints and reduce study length. Emerging proteomic markers of neuronal loss and glial activity in cerebrospinal fluid, a cortical signature derived from advanced structural and functional MRI, and the development of more sensitive measurements of lower motor neuron physiology are leading a new phase of biomarker-driven therapeutic discovery.
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