Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

Overhoff, M.; Tellkamp, F.; Hess, S.; Tutas, J.; Tolve, M.; Faerfers, M.; Ickert, L.; Mohammadi, M.; De Bruyckere, E.; Kallergi, E.; Dekk Vedove, A.; Nikoletopoulou, V.; Wirth, B.; Isensee, J.; Hucho, T.; Puchkov, D.; Isbrandt, D.; Krueger, M.; Kloppenburg, P.; Kononenko, N.

doi:10.1101/2022.02.11.480034

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bioRxiv · 10.1101/2022.02.11.480034

Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling

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Abstract

Autophagy provides nutrients during starvation and eliminates detrimental cellular components. However, accumulating evidence indicates that autophagy is not merely a housekeeping process. Here, we show that the protein AuTophaGy 5 (ATG5) functions in neurons to regulate the 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 the cAMP/PKA-dependent phosphorylation of postsynaptic cytoskeletal proteins mediating AMPAR trafficking. Glutamatergic neurons-confined ATG5 deletion 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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Overhoff, M., Tellkamp, F., Hess, S., Tutas, J., Tolve, M., Faerfers, M., Ickert, L., Mohammadi, M., De Bruyckere, E., Kallergi, E., Dekk Vedove, A., Nikoletopoulou, V., Wirth, B., Isensee, J., Hucho, T., Puchkov, D., Isbrandt, D., Krueger, M., Kloppenburg, P., Kononenko, N.. 2022-02-11. Autophagy regulates neuronal excitability by controlling cAMP/Protein Kinase A signaling. https://doi.org/10.1101/2022.02.11.480034

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