Critical role for Piccolo in synaptic vesicle retrieval.
Animals
Axons
/ metabolism
Cytoskeletal Proteins
/ metabolism
DNA Transposable Elements
/ genetics
Endosomes
/ metabolism
GTP Phosphohydrolases
/ metabolism
Gene Knockout Techniques
Guanosine Diphosphate
/ metabolism
Models, Biological
Mutagenesis
/ genetics
Neuropeptides
/ metabolism
Phosphatidylinositol Phosphates
/ metabolism
Rats
Synaptic Vesicles
/ metabolism
Synaptophysin
/ metabolism
Vesicular Transport Proteins
/ metabolism
rab5 GTP-Binding Proteins
/ metabolism
Piccolo
Rab5
early endosomes
neuroscience
rat
recycling
synaptic vesicles
Journal
eLife
ISSN: 2050-084X
Titre abrégé: Elife
Pays: England
ID NLM: 101579614
Informations de publication
Date de publication:
10 05 2019
10 05 2019
Historique:
received:
06
03
2019
accepted:
09
05
2019
pubmed:
11
5
2019
medline:
26
2
2020
entrez:
11
5
2019
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 31074746
doi: 10.7554/eLife.46629
pii: 46629
pmc: PMC6541439
doi:
pii:
Substances chimiques
Cytoskeletal Proteins
0
DNA Transposable Elements
0
Neuropeptides
0
Pclo protein, rat
0
Phosphatidylinositol Phosphates
0
Rabac1 protein, rat
0
Synaptophysin
0
Vesicular Transport Proteins
0
phosphatidylinositol 3-phosphate
0
Guanosine Diphosphate
146-91-8
GTP Phosphohydrolases
EC 3.6.1.-
rab5 GTP-Binding Proteins
EC 3.6.5.2
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Deutsche Forschungsgemeinschaft
ID : SFB958
Pays : International
Organisme : European Research Council
ID : ERC Advanced
Pays : International
Organisme : Norwegian Cancer Society
ID : Early carrier development grant
Pays : International
Organisme : NIH HHS
ID : R01HD053889
Pays : United States
Organisme : NCRR NIH HHS
ID : R24RR03232601
Pays : United States
Organisme : NIH Office of the Director
ID : R24OD011108
Pays : International
Organisme : European Research Council
ID : ERC Advanced ERC-2011-AdG 294742
Pays : International
Organisme : Bundesministerium für Bildung und Forschung
ID : NGFN-2 NGFNplus - ENGINE
Pays : International
Organisme : NIH HHS
ID : R01HD061575
Pays : United States
Organisme : Norwegian Cancer Society
ID : early carrier development grant
Pays : International
Organisme : National Institute of Health
ID : R01HD053889 and R01HD061575
Pays : International
Organisme : The Office of the Director
ID : R24OD011108
Pays : International
Organisme : European Research Council
ID : ERC Advanced,ERC-2011-AdG 294742
Pays : International
Organisme : Bundesministerium für Bildung und Forschung
ID : NGFN-2,NGFNplus - ENGINE
Pays : International
Informations de copyright
© 2019, Ackermann et al.
Déclaration de conflit d'intérêts
FA, KS, CB, ZI, FH, CR, CG No competing interests declared
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