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000165350 037__ $$aDZNE-2022-01627
000165350 041__ $$aEnglish
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000165350 1001_ $$00000-0002-4208-8632$$aOverhoff, Melina$$b0
000165350 245__ $$aAutophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse.
000165350 260__ $$aHoboken, NJ [u.a.]$$bWiley$$c2022
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000165350 520__ $$aAutophagy 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.
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000165350 650_7 $$2Other$$aPKA
000165350 650_7 $$2Other$$aautophagy
000165350 650_7 $$2Other$$abrain
000165350 650_7 $$2Other$$aphosphorylation
000165350 650_7 $$2Other$$asynapse
000165350 650_2 $$2MeSH$$aMice
000165350 650_2 $$2MeSH$$aAnimals
000165350 650_2 $$2MeSH$$aSynapses: metabolism
000165350 650_2 $$2MeSH$$aNeurons: metabolism
000165350 650_2 $$2MeSH$$aCyclic AMP-Dependent Protein Kinases: metabolism
000165350 650_2 $$2MeSH$$aSignal Transduction
000165350 650_2 $$2MeSH$$aAutophagy
000165350 7001_ $$00000-0002-0473-7320$$aTellkamp, Frederik$$b1
000165350 7001_ $$00000-0001-6085-5156$$aHess, Simon$$b2
000165350 7001_ $$00000-0002-0893-2967$$aTolve, Marianna$$b3
000165350 7001_ $$aTutas, Janine$$b4
000165350 7001_ $$aFaerfers, Marcel$$b5
000165350 7001_ $$aIckert, Lotte$$b6
000165350 7001_ $$00000-0003-1755-108X$$aMohammadi, Milad$$b7
000165350 7001_ $$aDe Bruyckere, Elodie$$b8
000165350 7001_ $$aKallergi, Emmanouela$$b9
000165350 7001_ $$00000-0003-4771-9808$$aDelle Vedove, Andrea$$b10
000165350 7001_ $$aNikoletopoulou, Vassiliki$$b11
000165350 7001_ $$00000-0003-4051-5191$$aWirth, Brunhilde$$b12
000165350 7001_ $$aIsensee, Joerg$$b13
000165350 7001_ $$00000-0002-4147-9308$$aHucho, Tim$$b14
000165350 7001_ $$00000-0001-8341-4847$$aPuchkov, Dmytro$$b15
000165350 7001_ $$0P:(DE-2719)2810976$$aIsbrandt, Dirk$$b16$$udzne
000165350 7001_ $$aKrueger, Marcus$$b17
000165350 7001_ $$00000-0002-4554-404X$$aKloppenburg, Peter$$b18
000165350 7001_ $$00000-0002-3425-6659$$aKononenko, Natalia L$$b19
000165350 773__ $$0PERI:(DE-600)1467419-1$$a10.15252/embj.2022110963$$n22$$pe110963$$tThe EMBO journal$$v41$$x0261-4189$$y2022
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