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Elife. 2019 May 10;8. pii: e46629. doi: 10.7554/eLife.46629. [Epub ahead of print]

Critical role for piccolo in synaptic vesicle retrieval.

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German Center for Neurodegenerative Diseases (DZNE), Charité Medical University, Berlin, Germany.
Center for Cancer Biomedicine, Norwegian Radium Hospital, University of Oslo, Oslo, Norway.
Max-Delbrück Center for Molecular Medicine in the Helmholtz Society, Berlin, Germany.
Department of Obstetrics and Gynecology, University of Texas Southwestern, Dallas, United States.
Institut für Neurophysiologie, Charité-Universitätsmedizin Berlin, Berlin, Germany.


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.


neuroscience; rat

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