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

Lee, Y.-K.; Xiao, C.; Zhou, X.; Wang, L.; McReynolds, M. G.; Wu, Z.; Purisic, E.; Kim, H.; Li, X.; Pang, Z. P.; Dai, J.; Peng, J.; Yang, N.; Yue, Z.

doi:10.1101/2024.12.30.630813

bioRxiv · 10.1101/2024.12.30.630813

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

Lee, Y.-K.·Xiao, C.·Zhou, X.·Wang, L.·McReynolds, M. G.·Wu, Z.·Purisic, E.·Kim, H.·Li, X.·Pang, Z. P.·Dai, J.·Peng, J.·Yang, N.·Yue, Z.

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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) adaptor, 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 delineated a central role of AKAP11 in coupling PKA kinase network regulation to synaptic transmission. Loss of AKAP11 distorted compartment-specific PKA and GSK3/{beta} activities and impaired cellular functions that significantly overlap with pathways associated with BD and SCZ. Moreover, we identified interactions between AKAP11, the PKA-RI adaptor SPHKAP, and the ER-resident autophagy-related proteins VAPA/B, which co-adapt and mediate PKA-RI complex degradation in neurons. Notably, AKAP11 deficiency impaired neurotransmission, providing key insights into the mechanism underlying AKAP11-associated psychiatric diseases.

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Lee, Y.-K., Xiao, C., Zhou, X., Wang, L., McReynolds, M. G., Wu, Z., Purisic, E., Kim, H., Li, X., Pang, Z. P., Dai, J., Peng, J., Yang, N., Yue, Z.. 2024-12-31. Bipolar and schizophrenia risk gene AKAP11 encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission. https://doi.org/10.1101/2024.12.30.630813

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