title: The proteasome controls presynaptic differentiation through modulation of an on-site pool of polyubiquitinated conjugates.
abstract: Differentiation of the presynaptic terminal is a complex and rapid event that normally occurs in spatially specific axonal regions distant from the soma; thus, it is believed to be dependent on intra-axonal mechanisms. However, the full nature of the local events governing presynaptic assembly remains unknown. Herein, we investigated the involvement of the ubiquitin-proteasome system (UPS), the major degradative pathway, in the local modulation of presynaptic differentiation. We found that proteasome inhibition has a synaptogenic effect on isolated axons. In addition, formation of a stable cluster of synaptic vesicles onto a postsynaptic partner occurs in parallel to an on-site decrease in proteasome degradation. Accumulation of ubiquitinated proteins at nascent sites is a local trigger for presynaptic clustering. Finally, proteasome-related ubiquitin chains (K11 and K48) function as signals for the assembly of presynaptic terminals. Collectively, we propose a new axon-intrinsic mechanism for presynaptic assembly through local UPS inhibition. Subsequent on-site accumulation of proteins in their polyubiquitinated state triggers formation of presynapses.
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal PhD Program in Experimental Biology and Biomedicine, Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Pinto
authors.affiliation: Instituto de Educação e Cidadania, 3770-033 Mamarrosa, Portugal.
authors.forename: Pedro L
authors.initials: PL
authors.lastname: Alves
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Martins
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal.
authors.forename: Joana R
authors.initials: JR
authors.lastname: Pedro
authors.affiliation: Institute of Advanced Machinery and Design, Seoul National University, Seoul 151-744, Korea.
authors.forename: Hyun R
authors.initials: HR
authors.lastname: Ryu
authors.affiliation: Institute of Advanced Machinery and Design, Seoul National University, Seoul 151-744, Korea Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul 151-744, Korea.
authors.forename: Noo Li
authors.initials: NL
authors.lastname: Jeon
authors.affiliation: Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC 27599.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Taylor
authors.affiliation: CNC - Center for Neuroscience and Cell Biology, University of Coimbra, 3004-517 Coimbra, Portugal Institute for Interdisciplinary Research, University of Coimbra, 3004-517 Coimbra, Portugal School of Allied Health Technologies, Polytechnic Institute of Porto, 4400-330 Vila Nova de Gaia, Portugal ramirodalmeida@gmail.com.
authors.forename: Ramiro D
authors.initials: RD
authors.lastname: Almeida
mesh_terms: D000818:Animals; D001369:Axons / Q000201:enzymology; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006624:Hippocampus / Q000187:drug effects / Q000196:embryology / Q000201:enzymology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008856:Microscopy, Fluorescence; D025821:Polyubiquitin / Q000378:metabolism*; D017729:Presynaptic Terminals / Q000187:drug effects / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000494:pharmacology; D059748:Proteolysis; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013572:Synaptic Vesicles / Q000201:enzymology; D013997:Time Factors; D059008:Time-Lapse Imaging; D014162:Transfection; D057149:Ubiquitinated Proteins / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D008164:Luminescent Proteins; D061988:Proteasome Inhibitors; D011993:Recombinant Fusion Proteins; D057149:Ubiquitinated Proteins; D025821:Polyubiquitin; D046988:Proteasome Endopeptidase Complex