期刊
EMBO JOURNAL
卷 41, 期 22, 页码 -出版社
WILEY
DOI: 10.15252/embj.2022110963
关键词
autophagy; brain; phosphorylation; PKA; synapse
资金
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy [EXC 2030-390661388, KO 5091/4-1]
- Fritz Thyssen Foundation [Az. 10.18.1.036MN]
- Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) [431549029-SFB 1451]
- DFG [DFG-233886668/GRK1960, RTG-2550, 411422114-GRK 2550, INST 1856/71-1 FUGG]
- Koln Fortune (Faculty of Medicine and University Hospital Cologne, University of Cologne) [282/2021]
- ERC [714983]
- Projekt DEAL
- European Research Council (ERC) [714983] Funding Source: European Research Council (ERC)
This research reveals a new role of autophagy in regulating PKA signaling at neuronal synapses. Loss of ATG5 leads to synaptic accumulation of PKA-R1, affecting AMPAR trafficking and excitatory neurotransmission, potentially causing seizures.
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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据