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Autophagy regulates neuronal excitability by controlling cAMP/protein kinase A signaling at the synapse.
Overhoff, Melina; Tellkamp, Frederik; Hess, Simon; Tolve, Marianna; Tutas, Janine; Faerfers, Marcel; Ickert, Lotte; Mohammadi, Milad; De Bruyckere, Elodie; Kallergi, Emmanouela; Delle Vedove, Andrea; Nikoletopoulou, Vassiliki; Wirth, Brunhilde; Isensee, Joerg; Hucho, Tim; Puchkov, Dmytro; Isbrandt, Dirk; Krueger, Marcus; Kloppenburg, Peter; Kononenko, Natalia L.
Afiliación
  • Overhoff M; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Tellkamp F; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Hess S; Faculty of Mathematics and Natural Sciences, Institute of Genetics, University of Cologne, Cologne, Germany.
  • Tolve M; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Tutas J; Faculty of Mathematics and Natural Sciences, Institute of Zoology, University of Cologne, Cologne, Germany.
  • Faerfers M; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Ickert L; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Mohammadi M; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • De Bruyckere E; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Kallergi E; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Delle Vedove A; Center for Physiology and Pathophysiology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Nikoletopoulou V; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Wirth B; Cologne Excellence Cluster Cellular Stress Response in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, Germany.
  • Isensee J; Département des Neurosciences Fondamentales, University of Lausanne, Lausanne, Switzerland.
  • Hucho T; Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Puchkov D; Département des Neurosciences Fondamentales, University of Lausanne, Lausanne, Switzerland.
  • Isbrandt D; Faculty of Mathematics and Natural Sciences, Institute of Genetics, University of Cologne, Cologne, Germany.
  • Krueger M; Institute of Human Genetics, Center for Molecular Medicine Cologne, Center for Rare Diseases Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Kloppenburg P; Translational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
  • Kononenko NL; Translational Pain Research, Department of Anaesthesiology and Intensive Care Medicine, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
EMBO J ; 41(22): e110963, 2022 11 17.
Article en En | MEDLINE | ID: mdl-36217825
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sinapsis / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: EMBO J Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Sinapsis / Neuronas Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: EMBO J Año: 2022 Tipo del documento: Article País de afiliación: Alemania Pais de publicación: Reino Unido