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<p>Human genomic studies have identified protein-truncating variants in <i>AKAP11</i> 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 <i>AKAP11</i>-associated psychiatric diseases.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月28日

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  • 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,
  • Zhenyu Yue

摘要

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.