Tubular microdomains of Rab7-positive endosomes retrieve TrkA, a mechanism disrupted in Charcot-Marie-Tooth disease 2B

2021 | journal article; research paper

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​Tubular microdomains of Rab7-positive endosomes retrieve TrkA, a mechanism disrupted in Charcot-Marie-Tooth disease 2B​
Markworth, R.; Dambeck, V.; Steinbeck, L. M.; Koufali, A.; Bues, B.; Dankovich, T. M. & Wichmann, C.  et al.​ (2021) 
Journal of Cell Science134(20).​ DOI: https://doi.org/10.1242/jcs.258559 

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Markworth, Ronja; Dambeck, Vivian; Steinbeck, Lars Malte; Koufali, Angeliki; Bues, Bastian; Dankovich, Tal M.; Wichmann, Carolin ; Burk, Katja
Axonal survival and growth requires signalling from tropomyosin receptor kinases (Trks). To transmit their signals, receptor-ligand complexes are endocytosed and undergo retrograde trafficking to the soma, where downstream signalling occurs. Vesicles transporting neurotrophic receptors to the soma are reported to be Rab7-positive late endosomes and/or multivesicular bodies (MVBs), where receptors localize within so-called intraluminal vesicles (herein Rab7 corresponds to Rab7A unless specified otherwise). Therefore, one challenging question is how downstream signalling is possible given the insulating properties of intraluminal vesicles. In this study, we report that Rab7-positive endosomes and MVBs retrieve TrkA (also known as NTRK1) through tubular microdomains. Interestingly, this phenotype is absent for the EGF receptor. Furthermore, we found that endophilinA1, endophilinA2 and endophilinA3, together with WASH1 (also known as WASHC1), are involved in the tubulation process. In Charcot-Marie-Tooth disease 2B (CMT2B), a neuropathy of the peripheral nervous system, this tubulating mechanism is disrupted. In addition, the ability to tubulate correlates with the phosphorylation levels of TrkA as well as with neurite length in neuronal cultures from dorsal root ganglia. In all, we report a new retrieval mechanism of late Rab7-positive endosomes, which enables TrkA signalling and sheds new light onto how neurotrophic signalling is disrupted in CMT2B. This article has an associated First Person interview with the first author of the paper.
Issue Date
Journal of Cell Science 
SFB 1286: Quantitative Synaptologie 
SFB 1286 | A04: Aktivitätsabhängige morphologische Veränderungen am Endkolben von Held-Synapsen 
Working Group
RG Wichmann (Molecular Architecture of Synapses) 
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