Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice
- German Center for Neurodegenerative Diseases, Germany
- Charité - Universitätsmedizin Berlin, Germany
- Leibniz Institute for Neurobiology, Germany
Abstract
Mechanisms regulating the turnover of synaptic vesicle (SV) proteins are not well understood. They are thought to require poly-ubiquitination and degradation through proteasome, endo-lysosomal or autophagy-related pathways. Bassoon was shown to negatively regulate presynaptic autophagy in part by scaffolding Atg5. Here, we show that increased autophagy in Bassoon knockout neurons depends on poly-ubiquitination and that the loss of Bassoon leads to elevated levels of ubiquitinated synaptic proteins per se. Our data show that Bassoon knockout neurons have a smaller SV pool size and a higher turnover rate as indicated by a younger pool of SV2. The E3 ligase Parkin is required for increased autophagy in Bassoon-deficient neurons as the knockdown of Parkin normalized autophagy and SV protein levels and rescued impaired SV recycling. These data indicate that Bassoon is a key regulator of SV proteostasis and that Parkin is a key E3 ligase in the autophagy-mediated clearance of SV proteins.
Data availability
All data generated or analysed during this study are included in the manuscript.
Article and author information
Author details
Marisa M Brockmann
Kazi Atikur Rahman
Christian Rosenmund
Craig Curtis Garner
Funding
Federal Government of Germany (SFB958)
- Craig Curtis Garner
Federal Government of Germany (SFB779/B09)
- Eckart D Gundelfinger
BMBF (20150065)
- Eckart D Gundelfinger
BMBF (20150065)
- Karl-Heinz Smalla
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Eunjoon Kim, Institute for Basic Science, Korea Advanced Institute of Science and Technology, Republic of Korea
Ethics
Animal experimentation: Breeding of animals and experiments using animal material were carried out in accordance with the European Communities Council Directive (2010/63/EU) and approved by the local animal care committees of Sachsen-Anhalt or the animal welfare committee of Charité Medical University and the Berlin state government (protocol number: T0036/14, O0208/16).
Version history
- Received: March 3, 2020
- Accepted: May 2, 2020
- Accepted Manuscript published: May 4, 2020 (version 1)
- Version of Record published: May 14, 2020 (version 2)
Copyright
© 2020, Hoffmann-Conaway et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,718
- views
-
- 423
- downloads
-
- 41
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Parkin contributes to synaptic vesicle autophagy in Bassoon-deficient mice
eLife 9:e56590.
https://doi.org/10.7554/eLife.56590
Further reading
-
- Neuroscience
Vesicles within presynaptic terminals are thought to be segregated into a variety of readily releasable and reserve pools. The nature of the pools and trafficking between them is not well understood, but pools that are slow to mobilize when synapses are active are often assumed to feed pools that are mobilized more quickly, in a series. However, electrophysiological studies of synaptic transmission have suggested instead a parallel organization where vesicles within slowly and quickly mobilized reserve pools would separately feed independent reluctant- and fast-releasing subdivisions of the readily releasable pool. Here, we use FM-dyes to confirm the existence of multiple reserve pools at hippocampal synapses and a parallel organization that prevents intermixing between the pools, even when stimulation is intense enough to drive exocytosis at the maximum rate. The experiments additionally demonstrate extensive heterogeneity among synapses in the relative sizes of the slowly and quickly mobilized reserve pools, which suggests equivalent heterogeneity in the numbers of reluctant and fast-releasing readily releasable vesicles that may be relevant for understanding information processing and storage.
-
- Evolutionary Biology
- Neuroscience
Neuropeptides are ancient signaling molecules in animals but only few peptide receptors are known outside bilaterians. Cnidarians possess a large number of G protein-coupled receptors (GPCRs) – the most common receptors of bilaterian neuropeptides – but most of these remain orphan with no known ligands. We searched for neuropeptides in the sea anemone Nematostella vectensis and created a library of 64 peptides derived from 33 precursors. In a large-scale pharmacological screen with these peptides and 161 N. vectensis GPCRs, we identified 31 receptors specifically activated by 1 to 3 of 14 peptides. Mapping GPCR and neuropeptide expression to single-cell sequencing data revealed how cnidarian tissues are extensively connected by multilayer peptidergic networks. Phylogenetic analysis identified no direct orthology to bilaterian peptidergic systems and supports the independent expansion of neuropeptide signaling in cnidarians from a few ancestral peptide-receptor pairs.
