Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, the Netherlands; Department of Neurophysiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University, Heijendaalseweg 135, 6525 AJ, Nijmegen, the Netherlands.
Department of Molecular Animal Physiology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, Radboud University, Geert Grooteplein Zuid 26-28, 6525 GA, Nijmegen, the Netherlands.
Prog Neurobiol. 2021 Jul;202:102069. doi: 10.1016/j.pneurobio.2021.102069. Epub 2021 Apr 29.
During the process of neuronal outgrowth, developing neurons produce new projections, neurites, that are essential for brain wiring. Here, we discover a relatively late-evolved protein that we denote Ac45-related protein (Ac45RP) and that, surprisingly, drives neuronal outgrowth. Ac45RP is a paralog of the Ac45 protein that is a component of the vacuolar proton ATPase (V-ATPase), the main pH regulator in eukaryotic cells. Ac45RP mRNA expression is brain specific and coincides with the peak of neurogenesis and the onset of synaptogenesis. Furthermore, Ac45RP physically interacts with the V-ATPase V-sector and colocalizes with V in unconventional, but not synaptic, secretory vesicles of extending neurites. Excess Ac45RP enhances the expression of V-subunits, causes a more elaborate Golgi, and increases the number of cytoplasmic vesicular structures, plasma membrane formation and outgrowth of actin-containing neurites devoid of synaptic markers. CRISPR-cas9n-mediated Ac45RP knockdown reduces neurite outgrowth. We conclude that the novel vertebrate- and brain-specific Ac45RP is a V-interacting constituent of unconventional vesicular structures that drives membrane expansion during neurite outgrowth and as such may furnish a tool for future neuroregenerative treatment strategies.
在神经元生长的过程中，发育中的神经元会产生新的突起，即神经突，这对于大脑的布线至关重要。在这里，我们发现了一种相对较新进化的蛋白质，我们将其命名为 Ac45 相关蛋白（Ac45RP），它出人意料地驱动了神经元的生长。Ac45RP 是 Ac45 蛋白的同源物，后者是液泡质子 ATP 酶（V-ATPase）的一个组成部分，V-ATPase 是真核细胞中主要的 pH 调节剂。Ac45RP mRNA 的表达具有大脑特异性，与神经发生的高峰期和突触发生的开始时间一致。此外，Ac45RP 与 V-ATPase 的 V 区具有物理相互作用，并与 V 一起定位于延伸的神经突中非典型但非突触分泌小泡中。过量的 Ac45RP 会增强 V 亚基的表达，导致更精细的高尔基体，并增加细胞质囊泡结构、质膜形成和不含突触标记物的肌动蛋白富含神经突的生长。CRISPR-cas9n 介导的 Ac45RP 敲低会减少神经突的生长。我们得出结论，新型脊椎动物和大脑特异性 Ac45RP 是 V 相互作用的非典型囊泡结构的组成部分，它在神经突生长过程中驱动膜的扩展，因此可能为未来的神经再生治疗策略提供一种工具。
