TBK1 activity regulates the directionality of axonal transport of signalling endosomes
Year: 2026
Type: article
Abstract: The polarised and complex morphology of neurons pose massive challenges for efficient cargo delivery between the axon and soma, a process termed axonal transport. We have previously shown that the retrograde axonal transport of pro-survival, neurotrophic signalling endosomes relies on Rab7 in motor neurons, and that their trafficking is impaired in the early stages of amyotrophic lateral sclerosis (ALS) pathogenesis. Here, we report the effect of Rab7 phosphorylation on the transport of these signalling endosomes. We show that the ALS-linked kinase TBK1 phosphorylates Rab7 at S72 in neurons, altering its binding to cytoplasmic dynein adaptors. Accordingly, both TBK1 knockdown and the expression of a loss-of-function Rab7 mutant (S72E) induce aberrant bidirectional movement of signalling endosomes without modifying neuronal polarity or endosomal sorting. This alteration is specific for signalling endosomes, as axonal transport of lysosomes and mitochondria remain unaffected. We have therefore discovered a new TBK1 function that ensures the unidirectional transport of signalling endosomes, suggesting that reduced TBK1 activity determines retrograde transport dysfunctions and long-range signalling impairments. Summary Signalling endosomes travel from the distal axon to the cell body, exerting pro-survival functions. TBK1, an ALS-linked kinase, governs the directionality of signalling endosome transport in motor neurons by phosphorylating Rab7. Thus, loss of TBK1 function results in long-range signalling impairment.
Source: Life Science Alliance
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,500
Funders: Wellcome Trust, Target ALS, Brain Research UK, Motor Neurone Disease Association, Ministry of Trade, Industry and Energy, Korea Institute for Advancement of Technology, Consejo Nacional de Innovación, Ciencia y Tecnología, UK Dementia Research Institute, Medical Research Council, Comisión Nacional de Investigación Científica y Tecnológica
Awards: G122181709, G1380976197, G1480258113, Targeting axonal transport regulation by neurotrophic factors to treat peripheral nerve degeneration, G2249060276, G27671266, G2987602257, G3690655654, The mechanism controlling sorting and axonal retrograde transport in neurons., G5095621666, G5127843888, Identification of modifiers of the axonal transport pathway in health and disease, G6868616705, Expanding the proteomics and establishing top-down capabilities for the UCL Mass Spectrometry Science Technology Platform., Regulation of axonal transport by neurotrophic factors in health and disease, G7965334604, G9000037479
OpenAlex ID: W7128069376