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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$$c2019
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000140720 520__ $$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.
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000140720 542__ $$2Crossref$$i2019-05-10$$uhttp://creativecommons.org/licenses/by/4.0/
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000140720 650_2 $$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
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