Cell death and differentiationJul 16, 2026

Schizophrenia and bipolar risk gene AKAP11 helps maintain thinking skills by controlling cell cleanup processes

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 17, 2026

Abstract

Acute depletion of Akap11 in mouse hippocampus induces cognitive deficits and synaptic dysfunction.

Akap11 deficiency is linked to cognitive impairments through disrupted autophagic processes.
AKAP11 is shown to regulate the initiation of autophagy and lysosomal activity in various cell types, including neurons.
Increased phosphorylation of the transcription factor EB (TFEB) is observed with AKAP11 deficiency, which impairs its ability to promote autophagy and lysosome production.
A specific interaction between AKAP11 and the phosphatase PPP3CB is identified, indicating a pathway that regulates TFEB activity.
Inhibition of PPP3CB prevents the dephosphorylation of TFEB by AKAP11.
Activating TFEB in Akap11-deficient mice reduces the build-up of autophagy substrates and alleviates cognitive deficits.

Simplified

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.

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PubMed

Schizophrenia and bipolar risk gene AKAP11 helps maintain thinking skills by controlling cell cleanup processes

Abstract

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