小柯机器人

近日，美国怀特黑德生物医学研究所Olivia Corradin团队的研究表明，细胞类型特异性基因座内相互作用揭示出多发性硬化症中少突胶质细胞相关机制。相关论文于2020年4月3日在线发表在《细胞》杂志上。

据研究人员介绍，多发性硬化症（MS）是一种自身免疫性疾病，其特征在于攻击中枢神经系统（CNS）中的少突胶质细胞。尽管广泛使用免疫调节疗法，但由于髓磷脂无法再生和神经元丧失，患者仍可能面临进行性残疾，这提示了其他细胞病变的存在。

研究人员描述了一种确定特定细胞类型（疾病等位基因在这些细胞中发挥了致病作用）的通用方法。将这种方法应用于MS风险基因座，研究人员查明了70％的可能致病细胞类型。除了T细胞基因座外，他们意外地确定了髓样和CNS特异性风险基因座，包括两个调节少突胶质细胞转录暂停释放的位点。

功能研究表明，抑制转录延伸是阻止少突胶质细胞成熟的主要途径。此外，MS脑组织中的停顿释放因子经常失调。这些数据暗示了免疫系统外的细胞异常，并为治疗研发提供了新途径。

附：英文原文

Title: Cell Type-Specific Intralocus Interactions Reveal Oligodendrocyte Mechanisms in MS

Author: Daniel C. Factor, Anna M. Barbeau, Kevin C. Allan, Lucille R. Hu, Mayur Madhavan, An T. Hoang, Kathryn E.A. Hazel, Parker A. Hall, Sagar Nisraiyya, Fadi J. Najm, Tyler E. Miller, Zachary S. Nevin, Robert T. Karl, Bruna R. Lima, Yanwei Song, Alexandra G. Sibert, Gursimran K. Dhillon, Christina Volsko, Cynthia F. Bartels, Drew J. Adams, Ranjan Dutta, Michael D. Gallagher, William Phu, Alexey Kozlenkov, Stella Dracheva, Peter C. Scacheri, Paul J. Tesar, Olivia Corradin

Issue&Volume: 2020-04-03

Abstract: Multiple sclerosis (MS) is an autoimmune disease characterized by attack on oligodendrocyteswithin the central nervous system (CNS). Despite widespread use of immunomodulatorytherapies, patients may still face progressive disability because of failure of myelinregeneration and loss of neurons, suggesting additional cellular pathologies. Here,we describe a general approach for identifying specific cell types in which a diseaseallele exerts a pathogenic effect. Applying this approach to MS risk loci, we pinpointlikely pathogenic cell types for 70%. In addition to T cell loci, we unexpectedlyidentified myeloid- and CNS-specific risk loci, including two sites that dysregulatetranscriptional pause release in oligodendrocytes. Functional studies demonstratedinhibition of transcriptional elongation is a dominant pathway blocking oligodendrocytematuration. Furthermore, pause release factors are frequently dysregulated in MS braintissue. These data implicate cell-intrinsic aberrations outside of the immune systemand suggest new avenues for therapeutic development.

DOI: 10.1016/j.cell.2020.03.002

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30264-6