이유경 (Icahn School of Medicine at Mount Sinai) | 한빛사논문 > 한빛사

한빛사논문

조회157

Icahn School of Medicine at Mount Sinai

CV File

Nat. Commun., 28 November 2025;16,10792(2025) | https://doi.org/10.1038/s41467-025-66356-w Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission

You-Kyung Lee^1,2,11, Cong Xiao^1,2,11, Xiaoting Zhou^1,2, Le Wang³, Meghan McReynolds^4,5, Zhiping Wu^4,5, Xian Han^4,5, Eric Purisic^2,6, Henry Kim^1,2, Xianting Li^1,2, Zhiping Pang³, Jinye Dai^2,6, Junmin Peng^4,5, Nan Yang^2,7,8,9 & Zhenyu Yue^1,2,10

¹Department of Neurology, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²Department of Neuroscience, The Friedman BrainInstitute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
³Child Health Institute of New Jersey and Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ, USA.
⁴Department of Structural Biology,St. Jude Children’s Research Hospital, Memphis, TN, USA.
⁵Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, USA.
⁶Department of Pharmacological Sciences, The Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁷Black Family Stem Cell Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁸Alper Center for Neurodevelopment and Regeneration, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
⁹Institute for Regenerative Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁰Center for Parkinson’s Disease Neurobiology, New York, NY, USA.
¹¹These authors contributed equally: You-Kyung Lee, Cong Xiao.

Corresponding author
Correspondence to Zhenyu Yue.

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.

논문정보