Magini Alessandro, Polchi Alice, Di Meo Danila, Mariucci Giuseppina, Sagini Krizia, De Marco Federico, Cassano Tommaso, Giovagnoli Stefano, Dolcetta Diego, Emiliani Carla
Department of Chemistry, Biology and Biotechnology, University of Perugia, Via del Giochetto, 06122 Perugia, Italy.
Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123, Perugia, Italy.
Hum Mol Genet. 2017 Sep 1;26(17):3303-3312. doi: 10.1093/hmg/ddx214.
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by mutations in either of two genes, TSC1 or TSC2, resulting in the constitutive activation of the mammalian target of rapamycin complex 1 (mTORC1). mTOR inhibitors are now considered the treatment of choice for TSC disease. A major pathological feature of TSC is the development of subependymal giant cell astrocytomas (SEGAs) in the brain. Nowadays, it is thought that SEGAs could be a consequence of aberrant aggregation and migration of neural stem/progenitor cells (NSPCs). Therefore, reactivation of cell migration of NSPCs might be the crucial step for the treatment of patients. In order to identify potential in vitro targets activating migration, we generated Tsc1-deficient NSPCs. These cells summarize most of the biochemical and morphological characteristics of TSC neural cells, such as the mTORC1 activation, the formation of abnormally enlarged astrocytes-like cells, the reduction of autophagy flux and the impairment of cell migration. Moreover, nuclear translocation, namely activation of the transcription factor EB (TFEB) was markedly impaired. Herein, we show that compounds such as everolimus, ionomycin and curcumin, which directly or indirectly stimulate TFEB nuclear translocation, restore Tsc1-deficient NSPC migration. Our data suggest that reduction of TFEB activation, caused by mTORC1 hyperactivation, contributes to the migration deficit characterizing Tsc1-deficient NSPCs. The present work highlights TFEB as a druggable protein target for SEGAs therapy, which can be additionally or alternatively exploited for the mTORC1-directed inhibitory approach.
结节性硬化症（TSC）是一种常染色体显性遗传病，由TSC1或TSC2这两个基因中的任意一个发生突变引起，导致雷帕霉素复合物1（mTORC1）的组成性激活。mTOR抑制剂现在被认为是TSC疾病的首选治疗方法。TSC的一个主要病理特征是大脑中室管膜下巨细胞星形细胞瘤（SEGA）的形成。如今，人们认为SEGA可能是神经干/祖细胞（NSPC）异常聚集和迁移的结果。因此，重新激活NSPC的细胞迁移可能是治疗患者的关键步骤。为了确定激活迁移的潜在体外靶点，我们生成了Tsc1缺陷的NSPC。这些细胞概括了TSC神经细胞的大部分生化和形态特征，如mTORC1激活、异常增大的星形胶质细胞样细胞的形成、自噬通量的减少和细胞迁移的受损。此外，核转位，即转录因子EB（TFEB）的激活明显受损。在此，我们表明，诸如依维莫司、离子霉素和姜黄素等直接或间接刺激TFEB核转位的化合物可恢复Tsc1缺陷的NSPC迁移。我们的数据表明，mTORC1过度激活导致的TFEB激活减少，导致了Tsc1缺陷的NSPC的迁移缺陷。目前的工作强调了TFEB作为SEGA治疗的可药物化蛋白质靶点，其可额外或替代地用于mTORC1导向的抑制方法。
