Amyotrophic Lateral Sclerosis: Problems and Prospects
Amyotrophic Lateral Sclerosis: Problems and Prospects
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DOI：
10.1002/ana.24012
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发表时间：
2013-09-01
影响因子：
11.2
通讯作者：
Brown, Robert H., Jr.
中科院分区：
文献类型：
--
作者：
Sreedharan, Jemeen;Brown, Robert H., Jr.
肌萎缩侧索硬化症（amyotrophiclateralsclerosis，ALS）是一种致死性的运动神经元退行性疾病，可与额颞叶痴呆同时发生。对大约10%的显性遗传的ALS病例的遗传分析提供了对ALS病理生物学的深入了解。两大主题是显而易见的。其中之一，由SOD 1基因的研究提示，是蛋白质的构象不稳定性触发下游神经毒性过程。第二，从TDP 43，FUS和C9 orf 72基因的研究，是RNA加工的扰动可以在运动神经元中是非常不利的。一些研究支持非神经元细胞（小胶质细胞，星形胶质细胞，少突胶质细胞）参与ALS的退行性过程的概念。最近的数据也强调了轴突和远端运动神经元末梢分子事件的重要性。只有一种化合物，利鲁唑，被美国食品和药物管理局批准用于ALS;几种疗法正在临床试验中，包括2个间充质干细胞试验。ALS的挑战和未满足的需求强调了新研究方向的重要性：家族性和散发性ALS的大DNA集的高通量测序，这将定义候选ALS基因和途径的分数，并促进上位性和表观遗传学的研究;候选基因验证的基础设施，包括体外和体内建模;阐明致病分子事件并加速临床试验的有效生物标志物;从长远来看，是识别环境毒素的方法。ALS研究的空前强度和非凡技术的出现（快速，廉价的DNA测序;从皮肤来源的成纤维细胞中生产干细胞;沉默邪恶的突变基因）预示着创新ALS疗法的发现。《神经病学年鉴》2013;74：309-316
Amyotrophic lateral sclerosis (ALS) is a lethal degenerative disorder of motoneurons, which may occur concurrently with frontotemporal dementia. Genetic analyses of the approximate to 10% of ALS cases that are dominantly inherited provide insight into ALS pathobiology. Two broad themes are evident. One, prompted by investigations of the SOD1 gene, is that conformational instability of proteins triggers downstream neurotoxic processes. The second, from studies of the TDP43, FUS, and C9orf72 genes, is that perturbations of RNA processing can be highly adverse in motoneurons. Several investigations support the concept that non-neuronal cells (microglia, astroglia, oligodendroglia) participate in the degenerative process in ALS. Recent data also emphasize the importance of molecular events in the axon and distal motoneuron terminals. Only 1 compound, riluzole, is approved by the US Food and Drug Administration for ALS; several therapies are in clinical trials, including 2 mesenchymal stem cell trials. The challenges and unmet needs in ALS emphasize the importance of new research directions: high-throughput sequencing of large DNA sets of familial and sporadic ALS, which will define scores of candidate ALS genes and pathways and facilitate studies of epistasis and epigenetics; infrastructures for candidate gene validation, including in vitro and in vivo modeling; valid biomarkers that elucidate causative molecular events and accelerate clinical trials; and in the long term, methods to identify environmental toxins. The unprecedented intensity of research in ALS and the advent of extraordinary technologies (rapid, inexpensive DNA sequencing; stem cell production from skin-derived fibroblasts; silencing of miscreant mutant genes) bode well for discovery of innovative ALS therapies. Ann Neurol 2013;74:309-316