Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission
Year: 2025
Type: article
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.
Source: Nature Communications
Authors: 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
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: G1579802114, G1677527330, G2353825758, G2445224069, Determining Selective Autophagy Kinase in Modulating Neurotoxicity in Huntington's Disease Model, Determining neuroprotective autophagy functions using different types of human neurons, G38585577, G456999112, G4852168507, Cellular consequences and convergent biology of schizophrenia-associated rare variants in the diverse GPC cohort, Neuronal Autophagy: a Cell-Autonomous Protection Mechanism, Assay and Data Generation Center (ADGC) for the Model of iPSC-derived Neurons for NPD (MiNND), Loss-of-Function Analyses of SETD1A in Human Neural Models
OpenAlex ID: W4416796061