title: Bassoon Controls Presynaptic Autophagy through Atg5.
abstract: Mechanisms regulating the surveillance and clearance of synaptic proteins are not well understood. Intriguingly, the loss of the presynaptic active zone proteins Piccolo and Bassoon triggers the loss of synaptic vesicles (SVs) and compromises synaptic integrity. Here we report that the destruction of SVs in boutons lacking Piccolo and Bassoon was associated with the induction of presynaptic autophagy, a process that depended on poly-ubiquitination, but not the E3 ubiquitin ligase Siah1. Surprisingly, gain or loss of function (LOF) of Bassoon alone suppressed or enhanced presynaptic autophagy, respectively, implying a fundamental role for Bassoon in the local regulation of presynaptic autophagy. Mechanistically, Bassoon was found to interact with Atg5, an E3-like ligase essential for autophagy, and to inhibit the induction of autophagy in heterologous cells. Importantly, Atg5 LOF as well as targeting an Atg5-binding peptide derived from Bassoon inhibited presynaptic autophagy in boutons lacking Piccolo and Bassoon, providing insights into the molecular mechanisms regulating presynaptic autophagy.
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Veteran's Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA.
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Okerlund
authors.affiliation: German Center for Neurodegenerative Diseases (DZNE), Berlin 10117, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Schneider
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sergio
authors.initials: S
authors.lastname: Leal-Ortiz
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg 39118, Germany.
authors.forename: Carolina
authors.initials: C
authors.lastname: Montenegro-Venegas
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Sally A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Loren C
authors.initials: LC
authors.lastname: Garner
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Clarissa L
authors.initials: CL
authors.lastname: Waites
authors.affiliation: Leibniz Institute for Neurobiology, Magdeburg 39118, Germany; Center for Behavioral Brain Sciences & Medical Faculty of the Otto von Guericke University, Magdeburg 39106, Germany; German Center for Neurodegenerative Diseases (DZNE), Magdeburg 39120, Germany.
authors.forename: Eckart D
authors.initials: ED
authors.lastname: Gundelfinger
authors.affiliation: Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; Veteran's Administration Palo Alto Health Care System, Palo Alto, CA 94304, USA. Electronic address: rjreimer@stanford.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Reimer
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA; German Center for Neurodegenerative Diseases (DZNE), Berlin 10117, Germany. Electronic address: craig-curtis.garner@dzne.de.
authors.forename: Craig C
authors.initials: CC
authors.lastname: Garner
mesh_terms: D000818:Animals; D001343:Autophagy / Q000502:physiology*; D000071187:Autophagy-Related Protein 5 / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D017729:Presynaptic Terminals / Q000378:metabolism; D051381:Rats; D013572:Synaptic Vesicles / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: C545865:Atg5 protein, rat; D000071187:Autophagy-Related Protein 5; D009419:Nerve Tissue Proteins
keywords: Atg5; Bassoon; Piccolo; active zones; presynapse; synaptic autophagy; synaptic proteostasis; synaptic vesicles