Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 115, Issue 43, Pages E10177-E10186Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1809189115
Keywords
endocytosis; neuron; presynapse; vesicle; Rab11
Categories
Funding
- Wellcome Trust [204954/Z/16/Z]
- Marie Curie Initial Training Network [289581-NPlast]
- Medical Research Council UK [MC_UU_12016/5]
- Boehringer-Ingelheim
- GlaxoSmithKline
- Merck KGaA
- Wellcome Trust [204954/Z/16/Z] Funding Source: Wellcome Trust
- MRC [MC_UU_12016/5] Funding Source: UKRI
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Activity-dependent bulk endocytosis (ADBE) is the dominant mode of synaptic vesicle endocytosis during high-frequency stimulation, suggesting it should play key roles in neurotransmission during periods of intense neuronal activity. However, efforts in elucidating the physiological role of ADBE have been hampered by the lack of identified molecules which are unique to this endocytosis mode. To address this, we performed proteomic analysis on purified bulk endosomes, which are a key organelle in ADBE. Bulk endosomes were enriched via two independent approaches, a classical subcellular fractionation method and isolation via magnetic nanoparticles. There was a 77% overlap in proteins identified via the two protocols, and these molecules formed the ADBE core proteome. Bioinformatic analysis revealed a strong enrichment in cell adhesion and cytoskeletal and signaling molecules, in addition to expected synaptic and trafficking proteins. Network analysis identified Rab GTPases as a central hub within the ADBE proteome. Subsequent investigation of a subset of these Rabs revealed that Rab11 both facilitated ADBE and accelerated clathrin-mediated endocytosis. These findings suggest that the ADBE proteome will provide a rich resource for the future study of presynaptic function, and identify Rab11 as a regulator of presynaptic function.
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