000140720 001__ 140720 000140720 005__ 20240430120011.0 000140720 0247_ $$2doi$$a10.7554/eLife.46629 000140720 0247_ $$2pmid$$apmid:31074746 000140720 0247_ $$2pmc$$apmc:PMC6541439 000140720 0247_ $$2altmetric$$aaltmetric:60251519 000140720 037__ $$aDZNE-2020-07042 000140720 041__ $$aEnglish 000140720 082__ $$a600 000140720 1001_ $$0P:(DE-2719)2810967$$aAckermann, Frauke$$b0$$eFirst author$$udzne 000140720 245__ $$aCritical role for Piccolo in synaptic vesicle retrieval. 000140720 260__ $$aCambridge$$beLife Sciences Publications$$c2019 000140720 264_1 $$2Crossref$$3online$$beLife Sciences Publications, Ltd$$c2019-05-10 000140720 3367_ $$2DRIVER$$aarticle 000140720 3367_ $$2DataCite$$aOutput Types/Journal article 000140720 3367_ $$0PUB:(DE-HGF)16$$2PUB:(DE-HGF)$$aJournal Article$$bjournal$$mjournal$$s1714464544_8220 000140720 3367_ $$2BibTeX$$aARTICLE 000140720 3367_ $$2ORCID$$aJOURNAL_ARTICLE 000140720 3367_ $$00$$2EndNote$$aJournal Article 000140720 520__ $$aLoss 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. 000140720 536__ $$0G:(DE-HGF)POF3-341$$a341 - Molecular Signaling (POF3-341)$$cPOF3-341$$fPOF III$$x0 000140720 542__ $$2Crossref$$i2019-05-10$$uhttp://creativecommons.org/licenses/by/4.0/ 000140720 588__ $$aDataset connected to CrossRef, PubMed, 000140720 650_2 $$2MeSH$$aAnimals 000140720 650_2 $$2MeSH$$aAxons: metabolism 000140720 650_2 $$2MeSH$$aCytoskeletal Proteins: metabolism 000140720 650_2 $$2MeSH$$aDNA Transposable Elements: genetics 000140720 650_2 $$2MeSH$$aEndosomes: metabolism 000140720 650_2 $$2MeSH$$aGTP Phosphohydrolases: metabolism 000140720 650_2 $$2MeSH$$aGene Knockout Techniques 000140720 650_2 $$2MeSH$$aGuanosine Diphosphate: metabolism 000140720 650_2 $$2MeSH$$aModels, Biological 000140720 650_2 $$2MeSH$$aMutagenesis: genetics 000140720 650_2 $$2MeSH$$aNeuropeptides: metabolism 000140720 650_2 $$2MeSH$$aPhosphatidylinositol Phosphates: metabolism 000140720 650_2 $$2MeSH$$aRats 000140720 650_2 $$2MeSH$$aSynaptic Vesicles: metabolism 000140720 650_2 $$2MeSH$$aSynaptic Vesicles: ultrastructure 000140720 650_2 $$2MeSH$$aSynaptophysin: metabolism 000140720 650_2 $$2MeSH$$aVesicular Transport Proteins: metabolism 000140720 650_2 $$2MeSH$$arab5 GTP-Binding Proteins: metabolism 000140720 7001_ $$0P:(DE-HGF)0$$aSchink, Kay Oliver$$b1 000140720 7001_ $$0P:(DE-2719)2811027$$aBruns, Christine$$b2$$udzne 000140720 7001_ $$aIzsvák, Zsuzsanna$$b3 000140720 7001_ $$aHamra, F Kent$$b4 000140720 7001_ $$aRosenmund, Christian$$b5 000140720 7001_ $$0P:(DE-2719)2810922$$aGarner, Craig Curtis$$b6$$eLast author$$udzne 000140720 77318 $$2Crossref$$3journal-article$$a10.7554/elife.46629$$b : eLife Sciences Publications, Ltd, 2019-05-10$$teLife$$v8$$x2050-084X$$y2019 000140720 773__ $$0PERI:(DE-600)2687154-3$$a10.7554/eLife.46629$$gVol. 8, p. 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