Ruhr-Universität Bochum, Faculty of Chemistry and Biochemistry, Department of Biochemistry II-Molecular Neurobiochemistry, 44801 Bochum, Germany.
Laboratoire Physico-Chimie, Institut Curie, CNRS UMR168, PSL Research University, Universite Pierre et Marie Curie-Paris, 75005 Paris, France.
Int J Mol Sci. 2018 Dec 14;19(12):4052. doi: 10.3390/ijms19124052.
Cellular activation of RAS GTPases into the GTP-binding "ON" state is a key switch for regulating brain functions. Molecular protein structural elements of rat sarcoma (RAS) and RAS homolog protein enriched in brain (RHEB) GTPases involved in this switch are discussed including their subcellular membrane localization for triggering specific signaling pathways resulting in regulation of synaptic connectivity, axonal growth, differentiation, migration, cytoskeletal dynamics, neural protection, and apoptosis. A beneficial role of neuronal H-RAS activity is suggested from cellular and animal models of neurodegenerative diseases. Recent experiments on optogenetic regulation offer insights into the spatiotemporal aspects controlling RAS/mitogen activated protein kinase (MAPK) or phosphoinositide-3 kinase (PI3K) pathways. As optogenetic manipulation of cellular signaling in deep brain regions critically requires penetration of light through large distances of absorbing tissue, we discuss magnetic guidance of re-growing axons as a complementary approach. In Parkinson's disease, dopaminergic neuronal cell bodies degenerate in the substantia nigra. Current human trials of stem cell-derived dopaminergic neurons must take into account the inability of neuronal axons navigating over a large distance from the grafted site into striatal target regions. Grafting dopaminergic precursor neurons directly into the degenerating substantia nigra is discussed as a novel concept aiming to guide axonal growth by activating GTPase signaling through protein-functionalized intracellular magnetic nanoparticles responding to external magnets.
细胞中 RAS GTP 酶的激活使其进入 GTP 结合的“开启”状态，是调节大脑功能的关键开关。本文讨论了参与这一转换的大鼠肉瘤（RAS）和富含大脑的 RAS 同源蛋白（RHEB）GTP 酶的分子蛋白结构元素，包括它们的亚细胞膜定位，以触发特定的信号通路，从而调节突触连接、轴突生长、分化、迁移、细胞骨架动态、神经保护和细胞凋亡。神经细胞 H-RAS 活性的有益作用已在神经退行性疾病的细胞和动物模型中得到证实。最近关于光遗传学调节的实验为控制 RAS/丝裂原活化蛋白激酶（MAPK）或磷酸肌醇 3 激酶（PI3K）通路的时空方面提供了深入的见解。由于光遗传学对深部脑区细胞信号的调控需要光穿透吸收组织的长距离，我们讨论了再生轴突的磁引导作为一种互补方法。在帕金森病中，多巴胺能神经元细胞体在黑质中退化。目前，干细胞衍生的多巴胺能神经元的人体试验必须考虑到神经元轴突从移植部位导航到纹状体靶区的远距离能力不足的问题。将多巴胺能前体细胞直接移植到退化的黑质中，作为一种新的概念被提出来，旨在通过激活具有蛋白质功能化的细胞内磁性纳米粒子的 GTP 酶信号来引导轴突生长，这些磁性纳米粒子对外界磁体做出响应。
