Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis.
Emerging insights into the complex genetics and pathophysiology of amyotrophic lateral sclerosis.
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DOI：
10.1016/s1474-4422(21)00414-2
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发表时间：
2022-05
期刊：
影响因子：
48
通讯作者：
Feldman, Eva L.
中科院分区：
文献类型：
--
作者：
Goutman, Stephen A.;Hardiman, Orla;Al-Chalabi, Ammar;Chio, Adriano;Savelieff, Masha G.;Kiernan, Matthew C.;Feldman, Eva L.
ALS是一种致命的神经退行性疾病。ALS基因的发现，从SOD 1开始，开始相对缓慢。遗传技术的最新进展导致了多个新ALS基因的快速鉴定，以及对寡基因和多基因疾病风险的新理解。ALS基因与其他疾病的重叠揭示了神经变性的表型谱，更好地理解了基因型-表型关系。对ALS遗传结构的深入了解正在阐明各种突变所采取的详细分子步骤，以汇集在高度共享和经常性失调的病理生理学途径上。至关重要的是，ALS突变适用于新的基于基因的治疗选择，这是一种用于其他神经系统疾病的方法。最后，通过基因-时间-环境假说，终身环境暴露的总和--疾病组的影响已经成为一种紧急的ALS风险。我们预计，我们对ALS所有这些方面的理解的提高将导致期待已久的治疗和可改变风险的识别。
ALS is a fatal neurodegenerative disease. The discovery of ALS genes, commencing with SOD1, started relatively gradually. Recent advances in genetic technology have led to the rapid identification of multiple new ALS genes, and a new understanding of oligogenic and polygenic disease risk. Overlap of ALS genes with other illnesses is shedding light on the phenotypic spectrum of neurodegeneration, with a better understanding of genotype-phenotype relationships. A deepening knowledge of ALS genetic architecture is elucidating the detailed molecular steps various mutations take to converge on highly shared and recurrent dysregulated pathophysiological pathways. Of critical relevance, ALS mutations are amenable to novel gene-based therapeutic options, an approach in use for other neurological illnesses. Lastly, the influence of the exposome, the summation of lifetime environmental exposures, has grown as an emergent ALS risk through the gene-time-environment hypothesis. We anticipate our improved understanding of all these aspects of ALS will lead to long-awaited therapies and the identification of modifiable risks.