Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University, Schillerstr. 44, Munich 80336, Germany.
Mol Cell Neurosci. 2013 Sep;56:475-86. doi: 10.1016/j.mcn.2013.03.006. Epub 2013 Apr 2.
Fused in sarcoma (FUS) is a nuclear DNA/RNA binding protein that regulates different steps of gene expression, including transcription, splicing and mRNA transport. FUS has been implicated in neurodegeneration, since mutations in FUS cause familial amyotrophic lateral sclerosis (ALS-FUS) and lead to the cytosolic deposition of FUS in the brain and spinal cord of ALS-FUS patients. Moreover, FUS and two related proteins of the same protein family (FET family) are co-deposited in cytoplasmic inclusions in a subset of patients with frontotemporal lobar degeneration (FTLD-FUS). Cytosolic deposition of these otherwise nuclear proteins most likely causes the loss of a yet unknown essential nuclear function and/or the gain of a toxic function in the cytosol. Here we summarize what is known about the physiological functions of the FET proteins in the nucleus and cytoplasm and review the distinctive pathomechanisms that lead to the deposition of only FUS in ALS-FUS, but all three FET proteins in FTLD-FUS. We suggest that ALS-FUS is caused by a selective dysfunction of FUS, while FTLD-FUS may be caused by a dysfunction of the entire FET family. This article is part of a Special Issue entitled 'RNA and splicing regulation in neurodegeneration'.
融合在肉瘤（FUS）是一种核 DNA/RNA 结合蛋白，调节基因表达的不同步骤，包括转录、剪接和 mRNA 运输。FUS 与神经退行性疾病有关，因为 FUS 的突变导致家族性肌萎缩侧索硬化症（ALS-FUS），并导致 ALS-FUS 患者的大脑和脊髓中 FUS 的胞质沉积。此外，FUS 和同一蛋白家族（FET 家族）的两个相关蛋白在额颞叶变性（FTLD-FUS）患者的细胞质包涵体中共同沉积。这些本来在核内的蛋白的胞质沉积很可能导致未知的核内必需功能丧失和/或在细胞质中获得毒性功能。在这里，我们总结了 FET 蛋白在核内和胞质中的生理功能，回顾了导致 ALS-FUS 中仅沉积 FUS 而 FTLD-FUS 中沉积所有三种 FET 蛋白的独特病理机制。我们认为 ALS-FUS 是由 FUS 的选择性功能障碍引起的，而 FTLD-FUS 可能是由整个 FET 家族的功能障碍引起的。本文是题为“神经退行性疾病中的 RNA 和剪接调控”的特刊的一部分。
