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AP-1/σ1B-Dependent SV Protein Recycling Is Regulated in Early Endosomes and Is Coupled to AP-2 Endocytosis

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Abstract

Adaptor protein (AP)-1/σ1B−/− mice have reduced synaptic-vesicle (SV) recycling and increased endosomes. Mutant mice have impaired spatial memory, and σ1B-deficient humans have a severe mental retardation. In order to define these σ1B−/− ‘bulk’ endosomes and to determine their functions in SV recycling, we developed a protocol to separate them from the majority of the neuronal endosomes. The σ1B−/− ‘bulk’ endosomes proved to be classic early endosomes with an increase in the phospholipid phosphatidylinositol 3-phosphate (PI-3-P), which recruits proteins mediating protein sorting out of early endosomes into different routes. σ1B deficiency induced alterations in the endosomal proteome reveals two major functions: SV protein storage and sorting into endolysosomes. Alternative endosomal recycling pathways are not up-regulated, but certain SV proteins are misrouted. Tetraspanins are enriched in σ1B−/− synaptosomes, but not in their endosomes or in their clathrin-coated-vesicles (CCVs), indicating AP-1/σ1B-dependent sorting. Synapses contain also more AP-2 CCV, although it is expected that they contain less due to reduced SV recycling. Coat composition of these AP-2 CCVs is altered, and thus, they represent a subpopulation of AP-2 CCVs. Association of calmodulin-dependent protein kinase (CaMK)-IIα, −δ and casein kinase (CK)-IIα with the endosome/SV pool is altered, as well as 14-3-3η, indicating changes in specific signalling pathways regulating synaptic plasticity. The accumulation of early endosomes and endocytotic AP-2 CCV indicates the regulation of SV recycling via early endosomes by the interdependent regulation of AP-2-mediated endocytosis and AP-1/σ1B-mediated SV reformation.

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Acknowledgments

We thank numerous colleagues who provided us with anti-sera, and we apologise that we can not mention them here due to space limitations. Their names are given in the SI. We thank O. Bernhard and D. Hesse for excellent technical assistance. This work was supported by the DFG grants Schu 802/3-1 and 802/3-2 to PS.

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Authors and Affiliations

  1. Center for Biochemistry and Molecular Cell Biology, Department for Cellular Biochemistry, Georg-August University Göttingen, Humboldtallee 23, 37073, Göttingen, Germany

    Manuel Kratzke, Ermes Candiello, Bernhard Schmidt & Peter Schu

  2. The Max-Planck-Institute for Experimental Medicine, Proteomics, Hermann-Rein-Str. 3, 37073, Göttingen, Germany

    Olaf Jahn

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  1. Manuel Kratzke
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Correspondence to Peter Schu.

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Summary Statement

Deficiency in adaptor protein (AP)-1/σ1B leads to mental retardation and fewer synaptic vesicles but more endosomes and clathrin-coated-vesicles (CCVs). Endosomes mediate primarily synaptic vesicle protein degradation, not recycling into alternative pathways. AP-2 CCV accumulates indicating coupling of endo- and exocytosis.

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Kratzke, M., Candiello, E., Schmidt, B. et al. AP-1/σ1B-Dependent SV Protein Recycling Is Regulated in Early Endosomes and Is Coupled to AP-2 Endocytosis. Mol Neurobiol 52, 142–161 (2015). https://doi.org/10.1007/s12035-014-8852-0

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