Biology subjects

Mandell, K. P.

Publications and source records attributed to Mandell, K. P..

5 recordsLinked to original sources

bioRxiv2025

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

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 AKAP11s 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 AKAP11s 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.

cell biology↗

bioRxiv2025

Epigenetic changes, neuronal dysregulation and metabolomic abnormalities in Zmym2 mutant mice, a genetic model of schizophrenia and neurodevelopmental disorders

Loss-of-function mutations in ZMYM2 are associated with an increased risk of schizophrenia (SCZ) and neurodevelopmental disorders (NDD). ZMYM2 interacts with proteins involved in histone modification and gene regulation, including LSD1 and ADNP; however, its specific roles in the brain remain poorly understood. In this multi-omics study, we demonstrate that heterozygous knockout of Zmym2 in mice results in widespread disturbances in gene expression affecting diverse molecular pathways, including those related to histone modifications and neuronal activity. Proteomic analysis of synapses reveals dysregulation of lipid metabolism and neurofilament-associated pathways, while metabolomic profiling identifies alterations in sphingomyelin and ceramide levels. Furthermore, Zmym2 mutant mice exhibit abnormal brain oscillation patterns on EEG and locomotor hyperactivity in the open field test. Collectively, these findings underscore the critical role of ZMYM2 in brain development and function and highlight Zmym2 mutant mice as a genetic animal model for SCZ and NDD.

neuroscience↗

bioRxiv2024

Brain-region-specific changes and dysregulation of activity regulated genes in Gria3 mutant mice, a genetic animal model of schizophrenia

Protein-truncating variants in GRIA3 (encoding the GluA3/GluR3 subunit of -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors) are associated with substantially increased risk of schizophrenia (SCZ). Here we characterized Gria3 mutant mice carrying a protein-truncating mutation that mimics a SCZ-associated variant. Transcriptomic analysis revealed that activity-regulated genes are downregulated in cortical regions, while immune and glia-related pathways exhibit brain-region-specific changes. The transcriptomic changes in Gria3 mutant mice are remarkably different from those in Grin2a mutant mice, particularly in the prefrontal cortex, even though both encode glutamate receptors and are associated with SCZ risk. Proteomic analysis further demonstrated that loss-of-function of Gria3 profoundly alters the protein composition of synapses. These findings in a genetic mouse model provide potential insights into the pathophysiological mechanisms underlying SCZ.

neuroscience↗

bioRxiv2024

Elevated synaptic PKA activity and abnormal striatal dopamine signaling in Akap11 mutant mice, a genetic model of schizophrenia and bipolar disorder

AbstractLoss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatly increase the risk of bipolar disorder and schizophrenia. To determine the neurobiological functions of AKAP11, we conduct multi-omic and neurobiological analyses of Akap11 mutant mouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whose loss leads to dramatically increased levels of PKA subunits and phosphorylated PKA substrates, especially in synapses. Akap11 mutant mice show extensive transcriptomic changes throughout the brain, including prominent decreases in synapse-related genes sets. Gene expression is highly impacted in spiny projection neurons of the striatum, a brain region implicated in motivation, cognition and psychotic disorders. Real-time measurements of PKA activity reveal elevated basal PKA activity in the striatum of Akap11-/- mice, with exaggerated additional response to dopamine receptor antagonists. Behaviorally, Akap11 mutant mice show abnormally prolonged locomotor response to amphetamine, deficits in associative learning and contextual discrimination, as well as depression-like behaviors. Our study connects molecular changes to circuit dysfunction and behavioral disturbance in a genetically valid animal model of psychotic disorder.

neuroscience↗

bioRxiv2021

TAZ/TEAD complex regulates TGF-β1-mediated fibrosis in iPSC-derived renal organoids

Chronic kidney disease (CKD) progresses by replacement of functional tissue compartments with fibrosis, representing a maladaptive repair process. Shifting kidney repair towards a physiologically-intact architecture, rather than fibrosis, is key to blocking CKD progression. In this study, we developed a fibrosis model that uses human induced pluripotent stem cell (iPSC)-based three-dimensional renal organoids, in which exogenous TGF-{beta}1 induces production of extracellular matrix. In these organoids, TGF- {beta}1 increased transcription factor tafazzin (TAZ) expression. Further, in human kidney biopsies, nuclear TAZ expression was markedly increased in mild and moderate fibrosis. In cultured renal tubular cells expressing a fibrogenic program, TAZ formed a trimeric complex with phosphorylated mothers against decapentaplegic homolog 3 (p-SMAD3) and TEA domain protein (TEAD)-4. Overexpression of TEAD4 protein suppressed collagen-11 (COL1A1) promoter activity, and expression of TAZ attenuated this inhibition. INT-767, a dual bile acid receptor agonist binding farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5), decreased the TGF-{beta}1-induced increase in p-SMAD3 and TAZ, and preserved renal organoid architecture. These data demonstrate, in an iPSC-derived renal organoid fibrosis model, that INT767 prevents fibrosis programs early in the course of tubular injury through modulation of the TEAD4/TAZ pathway.

cell biology↗