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1.
J Cell Biol ; 219(7)2020 07 06.
Article in English | MEDLINE | ID: mdl-32369542

ABSTRACT

At presynaptic active zones, arrays of large conserved scaffold proteins mediate fast and temporally precise release of synaptic vesicles (SVs). SV release sites could be identified by clusters of Munc13, which allow SVs to dock in defined nanoscale relation to Ca2+ channels. We here show in Drosophila that RIM-binding protein (RIM-BP) connects release sites physically and functionally to the ELKS family Bruchpilot (BRP)-based scaffold engaged in SV recruitment. The RIM-BP N-terminal domain, while dispensable for SV release site organization, was crucial for proper nanoscale patterning of the BRP scaffold and needed for SV recruitment of SVs under strong stimulation. Structural analysis further showed that the RIM-BP fibronectin domains form a "hinge" in the protein center, while the C-terminal SH3 domain tandem binds RIM, Munc13, and Ca2+ channels release machinery collectively. RIM-BPs' conserved domain architecture seemingly provides a relay to guide SVs from membrane far scaffolds into membrane close release sites.


Subject(s)
Carrier Proteins/chemistry , Central Nervous System/metabolism , Cytoskeletal Proteins/chemistry , Drosophila Proteins/chemistry , Drosophila melanogaster/metabolism , Synapses/metabolism , Synaptic Vesicles/metabolism , rab3 GTP-Binding Proteins/chemistry , Animals , Animals, Genetically Modified , Binding Sites , Calcium Channels/genetics , Calcium Channels/metabolism , Carrier Proteins/genetics , Carrier Proteins/metabolism , Central Nervous System/ultrastructure , Cloning, Molecular , Cytoskeletal Proteins/genetics , Cytoskeletal Proteins/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/ultrastructure , Escherichia coli/genetics , Escherichia coli/metabolism , Female , Gene Expression Regulation , Genetic Vectors/chemistry , Genetic Vectors/metabolism , Larva/genetics , Larva/metabolism , Larva/ultrastructure , Male , Membrane Proteins/chemistry , Membrane Proteins/genetics , Membrane Proteins/metabolism , Nerve Tissue Proteins/chemistry , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Protein Binding , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Synapses/ultrastructure , Synaptic Transmission , Synaptic Vesicles/ultrastructure , rab3 GTP-Binding Proteins/genetics , rab3 GTP-Binding Proteins/metabolism
2.
Nat Commun ; 10(1): 1318, 2019 03 21.
Article in English | MEDLINE | ID: mdl-30899013

ABSTRACT

Macroautophagy is an evolutionarily conserved cellular maintenance program, meant to protect the brain from premature aging and neurodegeneration. How neuronal autophagy, usually loosing efficacy with age, intersects with neuronal processes mediating brain maintenance remains to be explored. Here, we show that impairing autophagy in the Drosophila learning center (mushroom body, MB) but not in other brain regions triggered changes normally restricted to aged brains: impaired associative olfactory memory as well as a brain-wide ultrastructural increase of presynaptic active zones (metaplasticity), a state non-compatible with memory formation. Mechanistically, decreasing autophagy within the MBs reduced expression of an NPY-family neuropeptide, and interfering with autocrine NPY signaling of the MBs provoked similar brain-wide metaplastic changes. Our results in an exemplary fashion show that autophagy-regulated signaling emanating from a higher brain integration center can execute high-level control over other brain regions to steer life-strategy decisions such as whether or not to form memories.


Subject(s)
Aging/metabolism , Autophagy/genetics , Drosophila melanogaster/metabolism , Memory/physiology , Mushroom Bodies/metabolism , Neuropeptide Y/genetics , Aging/genetics , Animals , Autocrine Communication/genetics , Autophagy-Related Proteins/antagonists & inhibitors , Autophagy-Related Proteins/genetics , Autophagy-Related Proteins/metabolism , Brain/cytology , Brain/metabolism , Drosophila Proteins/antagonists & inhibitors , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Gene Expression Regulation , Membrane Proteins/antagonists & inhibitors , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mushroom Bodies/cytology , Neurons/cytology , Neurons/metabolism , Neuropeptide Y/deficiency , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Synapses/metabolism , Synaptic Transmission
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