TY  - JOUR
AU  - Overhoff, Melina
AU  - Tellkamp, Frederik
AU  - Hess, Simon
AU  - Tolve, Marianna
AU  - Tutas, Janine
AU  - Faerfers, Marcel
AU  - Ickert, Lotte
AU  - Mohammadi, Milad
AU  - De Bruyckere, Elodie
AU  - Kallergi, Emmanouela
AU  - Delle Vedove, Andrea
AU  - Nikoletopoulou, Vassiliki
AU  - Wirth, Brunhilde
AU  - Isensee, Joerg
AU  - Hucho, Tim
AU  - Puchkov, Dmytro
AU  - Isbrandt, Dirk
AU  - Krueger, Marcus
AU  - Kloppenburg, Peter
AU  - Kononenko, Natalia L
TI  - Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse.
JO  - The EMBO journal
VL  - 41
IS  - 22
SN  - 0261-4189
CY  - Hoboken, NJ [u.a.]
PB  - Wiley
M1  - DZNE-2022-01627
SP  - e110963
PY  - 2022
AB  - 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.
KW  - Mice
KW  - Animals
KW  - Synapses: metabolism
KW  - Neurons: metabolism
KW  - Cyclic AMP-Dependent Protein Kinases: metabolism
KW  - Signal Transduction
KW  - Autophagy
KW  - PKA (Other)
KW  - autophagy (Other)
KW  - brain (Other)
KW  - phosphorylation (Other)
KW  - synapse (Other)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC9670194
C6  - pmid:36217825
DO  - DOI:10.15252/embj.2022110963
UR  - https://pub.dzne.de/record/165350
ER  -