Biochemistry and Molecular Mechanisms Lab, APTD, CSIR-National Institute for Interdisciplinary Science and Technology (CSIR-NIIST), Council of Scientific and Industrial Research (CSIR), Ministry of Science and Technology, Government of India, Industrial Estate PO, Thiruvananthapuram, Kerala, 695019, India.
Molecular Medicine, Applied Biology, Biomedical Technology Wing, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, 695012, India.
Neuromolecular Med. 2018 Mar;20(1):18-36. doi: 10.1007/s12017-018-8479-9. Epub 2018 Feb 8.
In eukaryotes, the cellular functions are segregated to membrane-bound organelles. This inherently requires sorting of metabolites to membrane-limited locations. Sorting the metabolites from ribosomes to various organelles along the intracellular trafficking pathways involves several integral cellular processes, including an energy-dependent step, in which the sorting of metabolites between organelles is catalyzed by membrane-anchoring protein Rab-GTPases (Rab). They contribute to relaying the switching of the secretory proteins between hydrophobic and hydrophilic environments. The intracellular trafficking routes include exocytic and endocytic pathways. In these pathways, numerous Rab-GTPases are participating in discrete shuttling of cargoes. Long-distance trafficking of cargoes is essential for neuronal functions, and Rabs are critical for these functions, including the transport of membranes and essential proteins for the development of axons and neurites. Rabs are also the key players in exocytosis of neurotransmitters and recycling of neurotransmitter receptors. Thus, Rabs are critical for maintaining neuronal communication, as well as for normal cellular physiology. Therefore, cellular defects of Rab components involved in neural functions, which severely affect normal brain functions, can produce neurological complications, including several neurodegenerative diseases. In this review, we provide a comprehensive overview of the current understanding of the molecular signaling pathways of Rab proteins and the impact of their defects on different neurodegenerative diseases. The insights gathered into the dynamics of Rabs that are described in this review provide new avenues for developing effective treatments for neurodegenerative diseases-associated with Rab defects.
在真核生物中，细胞功能被分隔到膜结合的细胞器中。这本质上需要将代谢物分拣到膜限制的位置。沿着细胞内运输途径将代谢物从核糖体分拣到各种细胞器，涉及几个完整的细胞过程，包括一个依赖能量的步骤，其中膜锚定蛋白 Rab-GTPases（Rab）催化代谢物在细胞器之间的分拣。它们有助于将分泌蛋白在疏水环境和亲水环境之间的切换。细胞内运输途径包括胞吐和胞吞途径。在这些途径中，许多 Rab-GTPases 参与货物的离散穿梭。货物的长距离运输对于神经元功能至关重要，Rab 对于这些功能至关重要，包括轴突和树突发育所需的膜和必需蛋白的运输。Rab 也是神经递质胞吐和神经递质受体再循环的关键参与者。因此，Rab 对于维持神经元通讯以及正常细胞生理学至关重要。因此，涉及神经功能的 Rab 成分的细胞缺陷严重影响正常大脑功能，会产生神经并发症，包括几种神经退行性疾病。在这篇综述中，我们全面概述了 Rab 蛋白的分子信号通路的当前理解，以及它们的缺陷对不同神经退行性疾病的影响。本综述中描述的 Rab 动力学的见解为开发与 Rab 缺陷相关的神经退行性疾病的有效治疗方法提供了新途径。
