German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
J Mol Med (Berl). 2013 Dec;91(12):1343-54. doi: 10.1007/s00109-013-1077-2. Epub 2013 Aug 24.
Mutations in fused in sarcoma (FUS) in a subset of patients with amyotrophic lateral sclerosis (ALS) linked this DNA/RNA-binding protein to neurodegeneration. Most of the mutations disrupt the nuclear localization signal which strongly suggests a loss-of-function pathomechanism, supported by cytoplasmic inclusions. FUS-positive neuronal cytoplasmic inclusions are also found in a subset of patients with frontotemporal lobar degeneration (FTLD). Here, we discuss recent data on the role of alternative splicing in FUS-mediated pathology in the central nervous system. Several groups have shown that FUS binds broadly to many transcripts in the brain and have also identified a plethora of putative splice targets; however, only ABLIM1, BRAF, Ewing sarcoma protein R1 (EWSR1), microtubule-associated protein tau (MAPT), NgCAM cell adhesion molecule (NRCAM), and netrin G1 (NTNG1) have been identified in at least three of four studies. Gene ontology analysis of all putative targets unanimously suggests a role in axon growth and cytoskeletal organization, consistent with the altered morphology of dendritic spines and axonal growth cones reported upon loss of FUS. Among the axonal targets, MAPT/tau and NTNG1 have been further validated in biochemical studies. The next challenge will be to confirm changes of FUS-mediated alternative splicing in patients and define their precise role in the pathophysiology of ALS and FTLD.
在肌萎缩侧索硬化症（ALS）患者的亚组中，融合肉瘤（FUS）的突变将这种 DNA/RNA 结合蛋白与神经退行性变联系起来。大多数突变破坏了核定位信号，强烈提示了一种功能丧失的发病机制，这一机制得到了细胞质包涵体的支持。在额颞叶变性（FTLD）患者的亚组中也发现了 FUS 阳性神经元细胞质包涵体。在这里，我们讨论了最近关于 FUS 介导的中枢神经系统病理学中可变剪接作用的研究数据。几个研究小组表明，FUS 广泛结合大脑中的许多转录本，并确定了大量可能的剪接靶标；然而，只有 ABLIM1、BRAF、Ewing 肉瘤蛋白 R1（EWSR1）、微管相关蛋白 tau（MAPT）、神经细胞黏附分子 NgCAM（NRCAM）和轴突导向因子 G1（NTNG1）在至少四项研究中的三项中得到了鉴定。所有假定靶标的基因本体分析一致表明，它们在轴突生长和细胞骨架组织中发挥作用，这与 FUS 缺失后报道的树突棘和轴突生长锥形态改变一致。在轴突靶标中，MAPT/tau 和 NTNG1 在生化研究中得到了进一步验证。下一个挑战将是确认患者中 FUS 介导的可变剪接变化，并确定它们在 ALS 和 FTLD 病理生理学中的精确作用。
