Schizophrenia and bipolar disorder risk gene AKAP11 sustains cognitive function by regulating TFEB-mediated autophagy.

Authors

Zhiqiang Deng, Yuxuan Kan, Jia Liu, Ka Yee Ying, Yuxiao Yang, Xinjie Guan, Xiaogang Xu, Chengfu Su, Jing Lu, Kejia Lu, Yinchi Chen, Senthilkumar Krishnamoorthi, Jia-Hong Lu, Ashok Iyaswamy, King-Ho Cheung, Ju-Xian Song, Zhenyu Yue, Min Li

Published in

Cell death and differentiation. Jul 16, 2026. Epub Jul 16, 2026.

Abstract

Schizophrenia (SCZ) and bipolar disorder (BD) share cognitive impairments and autophagy disruptions, with haploinsufficiency of AKAP11 (A-kinase anchoring protein 11) emerging as a major genetic risk factor for both disorders, though its functional role remains poorly understood. Here, we demonstrate that acute Akap11 depletion in the mouse hippocampus induces cognitive deficits, accompanied by synaptic dysfunction and autophagy dysregulation, implicating Akap11 deficiency in cognitive impairments via disrupted autophagic processes. Using in vitro models, we show that AKAP11 regulates autophagy initiation and lysosomal activity in various cell types, including neuronal cells. Mechanistically, AKAP11 deficiency results in increased phosphorylation of transcription factor EB (TFEB), impairing its nuclear translocation and downregulating its target genes critical for autophagy and lysosome biogenesis. Further, we identify an interaction between AKAP11 and PPP3CB, a phosphatase responsible for TFEB dephosphorylation, and demonstrate that inhibition of PPP3CB abrogates AKAP11-mediated TFEB dephosphorylation. Importantly, in vivo administration of a TFEB activator reduces the accumulation of autophagy substrates and mitigates cognitive impairments in Akap11-deficient mice, highlighting TFEB activation as a potential therapeutic strategy. Collectively, our findings establish AKAP11 as a key regulator of the autophagy-lysosome pathway and cognitive function, providing novel insights into the pathophysiology of SCZ and BD and suggesting therapeutic potential in targeting TFEB-mediated autophagy.

PMID:
42463582
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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