Department of Neuromuscular Diseases and UCL Queen Square Motor Neuron Disease Centre, UCL Queen Square Institute of Neurology, University College London, London, United Kingdom.
UK Dementia Research Institute at UCL, London, United Kingdom.
Elife. 2023 Mar 10;12:e81532. doi: 10.7554/eLife.81532.
Neurons process real-time information from axon terminals to coordinate gene expression, growth, and plasticity. Inputs from distal axons are encoded as a stream of endocytic organelles, termed signalling endosomes, targeted to the soma. Formation of these organelles depends on target-derived molecules, such as brain-derived neurotrophic factor (BDNF), which is recognised by TrkB receptors on the plasma membrane, endocytosed, and transported to the cell body along the microtubules network. Notwithstanding its physiological and neuropathological importance, the mechanism controlling the sorting of TrkB to signalling endosomes is currently unknown. In this work, we use primary mouse neurons to uncover the small GTPase Rab10 as critical for TrkB sorting and propagation of BDNF signalling from axon terminals to the soma. Our data demonstrate that Rab10 defines a novel membrane compartment that is rapidly mobilised towards the axon terminal upon BDNF stimulation, enabling the axon to fine-tune retrograde signalling depending on BDNF availability at the synapse. These results help clarifying the neuroprotective phenotype recently associated to Rab10 polymorphisms in Alzheimer's disease and provide a new therapeutic target to halt neurodegeneration.
神经元从轴突末梢实时处理信息，以协调基因表达、生长和可塑性。来自远端轴突的输入被编码为一连串的内吞细胞器，称为信号内体，靶向到胞体。这些细胞器的形成取决于来自靶标的分子，如脑源性神经营养因子 (BDNF)，它被质膜上的 TrkB 受体识别，内吞，并沿着微管网络运输到胞体。尽管 BDNF 在生理和神经病理学上很重要，但控制 TrkB 向信号内体分拣的机制目前尚不清楚。在这项工作中，我们使用原代小鼠神经元来揭示小 GTPase Rab10 对 TrkB 分拣和 BDNF 信号从轴突末梢到胞体传播的关键作用。我们的数据表明，Rab10 定义了一个新的膜区室，该膜区室在 BDNF 刺激下迅速向轴突末梢移动，使轴突能够根据突触处 BDNF 的可用性来微调逆行信号。这些结果有助于阐明最近与阿尔茨海默病中 Rab10 多态性相关的神经保护表型，并为阻止神经退行性变提供了一个新的治疗靶点。
