Critical role for piccolo in synaptic vesicle retrieval
- German Center for Neurodegenerative Diseases (DZNE), Charité Medical University, Germany
- University of Oslo, Norway
- Max-Delbrück Center for Molecular Medicine in the Helmholtz Society, Germany
- University of Texas Southwestern, United States
- Charité-Universitätsmedizin Berlin, Germany
Abstract
Loss of function of the active zone protein Piccolo has recently been linked to a disease, Pontocerebellar Hypoplasia type 3, which causes brain atrophy. Here, we address how Piccolo inactivation in rat neurons adversely affects synaptic function and thus may contribute to neuronal loss. Our analysis shows that Piccolo is critical for the recycling and maintenance of synaptic vesicles. We find that boutons lacking Piccolo have deficits in the Rab5/EEA1 dependent formation of early endosomes and thus the recycling of SVs. Mechanistically, impaired Rab5 function was caused by reduced synaptic recruitment of Pra1, known to interact selectively with the zinc finger domains of Piccolo. Importantly, over-expression of GTPase deficient Rab5 or the Znf1 domain of Piccolo restores the size and recycling of SV pools. These data provide a molecular link between the active zone and endosome sorting at synapses providing hints to how Piccolo contributes to developmental and psychiatric disorders.
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All data generated or analysed during this study are included in the manuscript.
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Author details
Christian Rosenmund
Funding
Deutsche Forschungsgemeinschaft (SFB958)
- Craig Curtis Garner
European Research Council (ERC Advanced)
- Christian Rosenmund
Norwegian Cancer Society (early carrier development grant)
- Kay Oliver Schink
National Institute of Health (R01HD053889 and R01HD061575)
- F Kent Hamra
National Center for Research Resources (R24RR03232601)
- F Kent Hamra
The Office of the Director (R24OD011108)
- F Kent Hamra
European Research Council (ERC Advanced,ERC-2011-AdG 294742)
- Zsuzsanna Izsvák
Bundesministerium für Bildung und Forschung (NGFN-2,NGFNplus - ENGINE)
- Zsuzsanna Izsvák
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All procedures for experiments involving animals, were approved by the animal welfare committee of Charité Medical University and the Berlin state government (protocol number: T0036/14, O0208/16).
Copyright
© 2019, Ackermann 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.
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Critical role for piccolo in synaptic vesicle retrieval
eLife 8:e46629.
https://doi.org/10.7554/eLife.46629
