Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel; Molecular Neuroscience Unit, Okinawa Institute of Science and Technology Graduate University, Kunigami-gun, Okinawa 904-0412, Japan.
Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
Neurobiol Dis. 2020 Jul;140:104816. doi: 10.1016/j.nbd.2020.104816. Epub 2020 Feb 20.
The cytoplasmic dynein motor complex transports essential signals and organelles from the cell periphery to the perinuclear region, hence is critical for the survival and function of highly polarized cells such as neurons. Dynein Light Chain Roadblock-Type 1 (DYNLRB1) is thought to be an accessory subunit required for specific cargos, but here we show that it is essential for general dynein-mediated transport and sensory neuron survival. Homozygous Dynlrb1 null mice are not viable and die during early embryonic development. Furthermore, heterozygous or adult knockdown animals display reduced neuronal growth, and selective depletion of Dynlrb1 in proprioceptive neurons compromises their survival. Conditional depletion of Dynlrb1 in sensory neurons causes deficits in several signaling pathways, including β-catenin subcellular localization, and a severe impairment in the axonal transport of both lysosomes and retrograde signaling endosomes. Hence, DYNLRB1 is an essential component of the dynein complex, and given dynein's critical functions in neuronal physiology, DYNLRB1 could have a prominent role in the etiology of human neurodegenerative diseases.
细胞质动力蛋白复合物将重要的信号和细胞器从细胞外周运输到核周区域，因此对神经元等高度极化细胞的存活和功能至关重要。动力蛋白轻链阻抑型 1（DYNLRB1）被认为是特定货物所需的辅助亚基，但我们在这里表明，它对一般的动力蛋白介导的运输和感觉神经元的存活是必需的。Dynlrb1 纯合缺失小鼠在胚胎发育早期不能存活并死亡。此外，杂合子或成年敲低动物表现出神经元生长减少，而对本体感受神经元中 Dynlrb1 的选择性耗竭会损害它们的存活。条件性敲低感觉神经元中的 Dynlrb1 会导致几种信号通路的缺陷，包括β-连环蛋白亚细胞定位，以及溶酶体和逆行信号内体的轴突运输严重受损。因此，DYNLRB1 是动力蛋白复合物的一个必需组成部分，鉴于动力蛋白在神经元生理学中的关键作用，DYNLRB1 在人类神经退行性疾病的病因学中可能具有突出作用。
