Overhoff, Melina ORCID: 0000-0002-4208-8632, Tellkamp, Frederik ORCID: 0000-0002-0473-7320, Hess, Simon ORCID: 0000-0001-6085-5156, Tolve, Marianna ORCID: 0000-0002-0893-2967, Tutas, Janine, Faerfers, Marcel, Ickert, Lotte, Mohammadi, Milad ORCID: 0000-0003-1755-108X, De Bruyckere, Elodie, Kallergi, Emmanouela, Delle Vedove, Andrea, Nikoletopoulou, Vassiliki, Wirth, Brunhilde ORCID: 0000-0003-4051-5191, Isensee, Joerg, Hucho, Tim ORCID: 0000-0002-4147-9308, Puchkov, Dmytro, Isbrandt, Dirk ORCID: 0000-0002-4720-1016, Krueger, Marcus, Kloppenburg, Peter and Kononenko, Natalia L. (2022). Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse. Embo J., 41 (22). HOBOKEN: WILEY. ISSN 1460-2075

Full text not available from this repository.

Abstract

Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, by combining mouse models of neuron-specific ATG5 deficiency in either excitatory or inhibitory neurons with quantitative proteomics, high-content microscopy, and live-imaging approaches, we show that autophagy protein ATG5 functions in neurons to regulate cAMP-dependent protein kinase A (PKA)-mediated phosphorylation of a synapse-confined proteome. This function of ATG5 is independent of bulk turnover of synaptic proteins and requires the targeting of PKA inhibitory R1 subunits to autophagosomes. Neuronal loss of ATG5 causes synaptic accumulation of PKA-R1, which sequesters the PKA catalytic subunit and diminishes cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins that mediate AMPAR trafficking. Furthermore, ATG5 deletion in glutamatergic neurons augments AMPAR-dependent excitatory neurotransmission and causes the appearance of spontaneous recurrent seizures in mice. Our findings identify a novel role of autophagy in regulating PKA signaling at glutamatergic synapses and suggest the PKA as a target for restoration of synaptic function in neurodegenerative conditions with autophagy dysfunction.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Overhoff, MelinaUNSPECIFIEDorcid.org/0000-0002-4208-8632UNSPECIFIED
Tellkamp, FrederikUNSPECIFIEDorcid.org/0000-0002-0473-7320UNSPECIFIED
Hess, SimonUNSPECIFIEDorcid.org/0000-0001-6085-5156UNSPECIFIED
Tolve, MariannaUNSPECIFIEDorcid.org/0000-0002-0893-2967UNSPECIFIED
Tutas, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Faerfers, MarcelUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ickert, LotteUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mohammadi, MiladUNSPECIFIEDorcid.org/0000-0003-1755-108XUNSPECIFIED
De Bruyckere, ElodieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kallergi, EmmanouelaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Delle Vedove, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nikoletopoulou, VassilikiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
Isensee, JoergUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hucho, TimUNSPECIFIEDorcid.org/0000-0002-4147-9308UNSPECIFIED
Puchkov, DmytroUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Isbrandt, DirkUNSPECIFIEDorcid.org/0000-0002-4720-1016UNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kloppenburg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kononenko, Natalia L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-681212
DOI: 10.15252/embj.2022110963
Journal or Publication Title: Embo J.
Volume: 41
Number: 22
Date: 2022
Publisher: WILEY
Place of Publication: HOBOKEN
ISSN: 1460-2075
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DEPENDENT PROTEIN-KINASE; RECEPTOR GLUR1 SUBUNIT; NEUROTRANSMITTER RELEASE; SURFACE EXPRESSION; AMPA; PKA; PHOSPHORYLATION; MECHANISMS; LOCALIZATION; TARGETMultiple languages
Biochemistry & Molecular Biology; Cell BiologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68121

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item