John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
Laboratory of Developmental Neurobiology, Division of Intramural Research, National Heart, Lung and Blood Institute, NIH, Bethesda, USA.
Nat Commun. 2020 Nov 5;11(1):5614. doi: 10.1038/s41467-020-19436-y.
Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin's endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system.
成年哺乳动物中枢神经系统轴突具有内在的再生能力差，因此轴突损伤会产生永久性后果。增强再生的一种方法是增加生长分子和细胞器的轴突供应。我们通过表达衔接分子 Protrudin 来实现这一目标，Protrudin 通常在非再生神经元中低水平表达。Protrudin 的过表达使体外原代皮质神经元和体内损伤的成年视神经中的中枢神经系统再生都非常强劲。Protrudin 的过表达促进了内质网、整合素和 Rab11 内涵体在远端轴突中的积累，而去除 Protrudin 的内质网定位、驱动蛋白结合或磷酸肌醇结合特性则消除了再生效应。这些结果表明，Protrudin 通过充当连接轴突细胞器、马达和膜的支架来促进再生，确立了这些细胞成分在介导成年中枢神经系统再生中的重要作用。
