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Rab10 regulates the sorting of internalised TrkB for retrograde axonal transport
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Abstract
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.
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LRRK2 activity plays a role in synaptic vesicle endocytosis, activation of autophagy, and axonal transport of growth factor receptors.
“LRRK2 activity plays a role in synaptic vesicle endocytosis, activation of autophagy, and axonal transport of growth factor receptors [2, 7, 10, 24, 25, 36, 51, 59, 62, 75, 77, 96].”
From Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain (2023) · cites this paper as [36]
The Discussion links LRRK2 activity to Rab10 phosphorylation and discusses possible effects on the axonal trafficking of TrkB, a growth factor receptor, but says the relevant transport mechanism remains under investigation. A reference title mentions LRRK2 in synaptic endocytosis; the paper's discussion does not establish the synaptic-vesicle claim, and the supplied passages do not support the autophagy claim. (LLM, conf=0.82)
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Endo-lysosomal dysregulations and late-onset Alzheimer’s disease: impact of genetic risk factors
Van Acker, Z. P., Bretou, M., & Annaert, W. (2019) · Molecular Neurodegeneration · doi:10.1186/s13024-019-0323-7 · Cited by 222
González-Gutiérrez, A., Lazo, O. M., & Bronfman, F. C. (2020) · The Journal of Neuroscience · doi:10.1523/jneurosci.2063-19.2020 · Cited by 38
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Cited by
Sorted by citations
Cellular and subcellular localization of Rab10 and phospho-T73 Rab10 in the mouse and human brain
Singh, V., Menard, M. A., Serrano, G. E., Beach, T. G., Zhao, H. T., Riley-DiPaolo, A., Subrahmanian, N., LaVoie, M. J., & Volpicelli-Daley, L. A. (2023) · Acta Neuropathologica Communications · doi:10.1186/s40478-023-01704-9 · Cited by 9
Metadata
- Authors
- Lazo, O. M., & Schiavo, G.
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2023-03-10
- Volume
- 12
- ISSN
- 2050-084X
- PMC
- PMC10005780
- Cited by
- 26
- References
- 2
- Language
- en
- Licence
- Funders
- Medical Research Council (MR/T001976/1)
- Wellcome Trust (107116/Z/15/Z, 223022/Z/21/Z)
- UK Dementia Research Institute Foundation (UKDRI-1005)
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