Abnormal Lipid Metabolism and Altered Neuronal Support by Astrocytes Lacking Akap11 , a Risk Gene for Schizophrenia and Bipolar Disorder

作者：Xiao‐Man Liu, Horia Pribiag, Deeksha Misri, Kwanho Kim, Kira A. Perzel Mandell, Bryan J. Song, David Graykowski, Olivia Seidel, Nolan D. Hartley, Mateo Herrera, Haiyun Xu, Matthew Tegtmeyer, Yanling Zhang, Lei Cui, Natalie M. Clark, Wei-Chao Huang, John Adeleye, Courtney Dennis, Lucas Dailey, Amy Deik, Lucia Inunciaga, Eivgeni Mashin, Sean Simmons, Jen Q. Pan, Ralda Nehme, Hasmik Keshishian, Steven A. Carr, Zhanyan Fu, Joshua Z. Levin, Clary B. Clish, Morgan Sheng · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2025 · DOI：10.1101/2025.04.25.650548 · 被引用次数：7 · 研究领域：Diet and metabolism studies、Birth, Development, and Health

Abstract A-Kinase Anchoring Protein 11 ( AKAP11 ) is a shared genetic risk factor for schizophrenia and bipolar disorder, yet its role in the brain remains poorly understood. Through multi-omic analysis of Akap11 mutant mouse brains and cultured astrocytes, we identified significant transcriptomic, proteomic, and metabolomic alterations. Key findings include the upregulation of cholesterol and fatty acid metabolic pathways, accumulation of lipid species such as cholesteryl esters, triacylglycerols, ceramides, and glycerophospholipids, and elevated levels of 3’,5’-cyclic AMP and protein kinase A (PKA) signaling. These metabolic perturbations manifested as increased lipid droplet accumulation in Akap11 mutant astrocytes, highlighting AKAP11’s critical role in regulating intracellular lipid homeostasis. Mechanistically, AKAP11 functions as an autophagy receptor mediating PKA degradation and interacts with endoplasmic reticulum-resident proteins VAP-A and VAP-B through its FFAT motif, providing possible molecular insight into AKAP11’s regulation of lipid metabolism. Co-culture experiments with mouse astrocytes and human induced pluripotent stem cell-derived neurons demonstrated that loss of Akap11 in astrocytes, relative to wild-type, increases excitatory neurotransmission and neuronal activity. Collectively, these findings link AKAP11-mediated lipid and synaptic dysregulation to psychiatric disease risk and highlight the potential role of astrocytes in these disorders.