TY  - JOUR
AU  - Ackermann, Frauke
AU  - Schink, Kay Oliver
AU  - Bruns, Christine
AU  - Izsvák, Zsuzsanna
AU  - Hamra, F Kent
AU  - Rosenmund, Christian
AU  - Garner, Craig Curtis
TI  - Critical role for Piccolo in synaptic vesicle retrieval.
JO  - eLife
VL  - 8
SN  - 2050-084X
CY  - Cambridge
PB  - eLife Sciences Publications
M1  - DZNE-2020-07042
SP  - e46629
PY  - 2019
AB  - 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.
KW  - Animals
KW  - Axons: metabolism
KW  - Cytoskeletal Proteins: metabolism
KW  - DNA Transposable Elements: genetics
KW  - Endosomes: metabolism
KW  - GTP Phosphohydrolases: metabolism
KW  - Gene Knockout Techniques
KW  - Guanosine Diphosphate: metabolism
KW  - Models, Biological
KW  - Mutagenesis: genetics
KW  - Neuropeptides: metabolism
KW  - Phosphatidylinositol Phosphates: metabolism
KW  - Rats
KW  - Synaptic Vesicles: metabolism
KW  - Synaptic Vesicles: ultrastructure
KW  - Synaptophysin: metabolism
KW  - Vesicular Transport Proteins: metabolism
KW  - rab5 GTP-Binding Proteins: metabolism
LB  - PUB:(DE-HGF)16
C6  - pmid:31074746
C2  - pmc:PMC6541439
DO  - DOI:10.7554/eLife.46629
UR  - https://pub.dzne.de/record/140720
ER  -