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@ARTICLE{Overhoff:165350,
author = {Overhoff, Melina and Tellkamp, Frederik and Hess, Simon and
Tolve, Marianna and Tutas, Janine and Faerfers, Marcel and
Ickert, Lotte and Mohammadi, Milad and De Bruyckere, Elodie
and Kallergi, Emmanouela and Delle Vedove, Andrea and
Nikoletopoulou, Vassiliki and Wirth, Brunhilde and Isensee,
Joerg and Hucho, Tim and Puchkov, Dmytro and Isbrandt, Dirk
and Krueger, Marcus and Kloppenburg, Peter and Kononenko,
Natalia L},
title = {{A}utophagy regulates neuronal excitability by controlling
c{AMP}/protein kinase {A} signaling at the synapse.},
journal = {The EMBO journal},
volume = {41},
number = {22},
issn = {0261-4189},
address = {Hoboken, NJ [u.a.]},
publisher = {Wiley},
reportid = {DZNE-2022-01627},
pages = {e110963},
year = {2022},
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.},
keywords = {Mice / Animals / Synapses: metabolism / Neurons: metabolism
/ Cyclic AMP-Dependent Protein Kinases: metabolism / Signal
Transduction / Autophagy / PKA (Other) / autophagy (Other) /
brain (Other) / phosphorylation (Other) / synapse (Other)},
cin = {AG Isbrandt},
ddc = {570},
cid = {I:(DE-2719)1011003},
pnm = {351 - Brain Function (POF4-351)},
pid = {G:(DE-HGF)POF4-351},
typ = {PUB:(DE-HGF)16},
pmc = {pmc:PMC9670194},
pubmed = {pmid:36217825},
doi = {10.15252/embj.2022110963},
url = {https://pub.dzne.de/record/165350},
}