Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission

You-Kyung Lee, Cong Xiao, Xiaoting Zhou, Le Wang, Meghan McReynolds, Zhiping Wu, Xian Han, Eric Purisic, Henry Kim, Xianting Li, Zhiping Pang, Jinye Dai, Junmin Peng, Nan Yang and Zhenyu Yue ()
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You-Kyung Lee: Icahn School of Medicine at Mount Sinai, Department of Neurology, The Friedman Brain Institute
Cong Xiao: Icahn School of Medicine at Mount Sinai, Department of Neurology, The Friedman Brain Institute
Xiaoting Zhou: Icahn School of Medicine at Mount Sinai, Department of Neurology, The Friedman Brain Institute
Le Wang: Rutgers University, Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School
Meghan McReynolds: St. Jude Children’s Research Hospital, Department of Structural Biology
Zhiping Wu: St. Jude Children’s Research Hospital, Department of Structural Biology
Xian Han: St. Jude Children’s Research Hospital, Department of Structural Biology
Eric Purisic: Icahn School of Medicine at Mount Sinai, Department of Neuroscience, The Friedman Brain Institute
Henry Kim: Icahn School of Medicine at Mount Sinai, Department of Neurology, The Friedman Brain Institute
Xianting Li: Icahn School of Medicine at Mount Sinai, Department of Neurology, The Friedman Brain Institute
Zhiping Pang: Rutgers University, Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School
Jinye Dai: Icahn School of Medicine at Mount Sinai, Department of Neuroscience, The Friedman Brain Institute
Junmin Peng: St. Jude Children’s Research Hospital, Department of Structural Biology
Nan Yang: Icahn School of Medicine at Mount Sinai, Department of Neuroscience, The Friedman Brain Institute
Zhenyu Yue: Icahn School of Medicine at Mount Sinai, Department of Neurology, The Friedman Brain Institute

Nature Communications, 2025, vol. 16, issue 1, 1-20

Abstract: Abstract Human genomic studies have identified protein-truncating variants in AKAP11 associated with both bipolar disorder (BD) and schizophrenia (SCZ), implicating a shared disease mechanism driven by loss-of-function. AKAP11, a protein kinase A (PKA) adapter, plays a key role in degrading the PKA-RI complex through selective autophagy. However, the neuronal functions of AKAP11 and the impact of its loss-of-function remains largely uncharacterized. Through multi-omics approaches, cell biology, and electrophysiology analysis in mouse models and human induced neurons, we delineate a central role of AKAP11 in coupling PKA kinase network regulation to synaptic transmission. Loss of AKAP11 distorts compartment-specific PKA and GSΚ3α/β activities and impairs cellular functions that significantly overlap with pathways associated with BD and SCZ. Moreover, we identify the interactions between AKAP11, the PKA-RI adapter SPHKAP, and the ER-resident autophagy-related proteins VAPA/B, which co-adapt and mediate PKA-RI complex degradation in neurons. Notably, AKAP11 deficiency impairs neurotransmission, providing key insights into the mechanism underlying AKAP11-associated psychiatric diseases.

Date: 2025
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DOI: 10.1038/s41467-025-66356-w

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